WO2019233438A1 - Kinase selective inhibitor - Google Patents

Kinase selective inhibitor Download PDF

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Publication number
WO2019233438A1
WO2019233438A1 PCT/CN2019/090131 CN2019090131W WO2019233438A1 WO 2019233438 A1 WO2019233438 A1 WO 2019233438A1 CN 2019090131 W CN2019090131 W CN 2019090131W WO 2019233438 A1 WO2019233438 A1 WO 2019233438A1
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compound
room temperature
salt
mmol
stereoisomer
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PCT/CN2019/090131
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French (fr)
Chinese (zh)
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潘峥婴
石莉扬
钟振鹏
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北京大学深圳研究生院
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Publication of WO2019233438A1 publication Critical patent/WO2019233438A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to a kinase selective inhibitor, a pharmaceutical composition comprising the same, and a medicinal use thereof.
  • Fibroblast growth factor receptor 4 is a protein encoded by the FGFR-4 gene in humans. This protein is a member of the fibroblast growth factor receptor family, in which the amino acid sequence is highly conserved among members throughout the evolution process. FGFR family members 1-4 have different ligand affinities and tissue distributions from each other.
  • the composition of the full-length representative protein is an extracellular region composed of three epiglobin-like domains, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain. The extracellular part of the protein interacts with fibroblast growth factor, triggering a downstream signaling cascade, and ultimately affecting mitosis and differentiation.
  • the genomic organization of the FGFR-4 gene includes 18 exons. Although alternative splicing has been observed, there is no evidence that the half-IgIII domain of the C-terminus of such proteins differs between the other three forms (referred to as FGFR1-3).
  • the invention describes inhibitors of FGFR-4.
  • the invention also describes pharmaceutical formulations comprising FGFR-4 inhibitors.
  • the present invention provides the following technical solutions:
  • G 1 and G 2 are independently, identically or differently selected from H, C (O) and S (O) 2 ;
  • L 1 and L 2 are independently of each other, identically or differently, selected from C 2-3 alkenyl, C 0-3 alkyl-C 2-3 alkenyl, and optionally substituted with C 1-3 alkyl C 1-3 alkyl-NHC (O) -C 2-3 alkenyl;
  • the premise is that when G 1 is H, L 1 does not exist, and when G 2 is H, L 2 does not exist.
  • Ar is a 5- or 6-membered monocyclic aromatic ring
  • halogen preferably -Cl
  • -OH -C 1-4 alkyl
  • -C 1-4 alkyloxy
  • n is an integer of 0,1,2,3,4,5;
  • W 1 is CH, CR 1 or N;
  • W 2 is CH, CR 1 or N;
  • W 3 is CH, CR 1 or N;
  • W 4 is CH, CR 1 or N;
  • W 5 is CH, CR 1 or N;
  • W 6 is CH, CR 1 or N;
  • W 7 is CH, CR 1 or N;
  • n is an integer of 0,1,2,3,4,5;
  • halogen preferably -Cl
  • -OH -C 1-4 alkyl
  • -C 1-4 alkyloxy
  • R 3 is selected from H and -C 1-4 alkyl.
  • G 2 is H, and L 2 does not exist.
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , and W 7 are all CH.
  • Embodiment 4 The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof,
  • R 3 is H.
  • Embodiment 7 The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof,
  • Embodiment 8 The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, Ar or Ar- (R 1 ) m is
  • Embodiment 9 The compound, salt or stereoisomer thereof according to any one of the foregoing embodiments, Ar or Ar- (R 1 ) m is
  • Embodiment 10 The compound according to any one of the foregoing embodiments, a salt thereof or a stereoisomer thereof, Ar or Ar- (R 1 ) m is
  • Embodiment 11 The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, Ar or Ar- (R 1 ) m is
  • Embodiment 12 The compound according to any one of the preceding embodiments, a salt thereof or a stereoisomer thereof, and R 2 or (R 2 ) n is H.
  • Embodiment 13 The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, and R 2 or (R 2 ) n is
  • Embodiment 14 The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, and R 2 or (R 2 ) n is
  • Embodiment 15 The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
  • Embodiment 16 The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
  • Embodiment 17 The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
  • Embodiment 18 The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
  • Embodiment 19 A compound, a salt thereof or a stereoisomer thereof, wherein the compound is selected from the following compounds 1-23:
  • Embodiment 20 A pharmaceutical composition comprising the compound according to any one of the preceding embodiments, a salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 21 The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to any one of the foregoing embodiments, is prepared for treatment by FGFR-4.
  • Pathological conditions conditions characterized by FGFR-4 overexpression, conditions characterized by FGFR4 amplification, conditions mediated by FGF19, conditions characterized by amplified FGF19, or conditions characterized by FGF19 overexpression Use.
  • Technical solution 22 The use according to any one of the preceding technical solutions, wherein the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma or hyperlipidemia.
  • FIG 1 illustrates the results of the "time-dependent inhibition experiment”.
  • the present invention provides a compound represented by the above formula (I) (including a stable isotope substitute thereof), a salt thereof, or a stereoisomer thereof, which is a FGFR-4 selective inhibitor.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I (including a stable isotope replacement thereof) or a pharmaceutically acceptable salt thereof, or a compound of formula II (including a stable isotope replacement thereof) or Its pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers include inert solid fillers or excipients and sterile aqueous or organic solutions.
  • the compound should be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage of the agent. Techniques for formulating and administering the compounds disclosed in the present invention are well known to those skilled in the art, and can be found, for example, in Remington: The Science and Practice of Pharmacy, Remington Pharmaceutical Science and Practice, 19th Edition, Mack Publishing Company, Easton, PA (1995).
  • the present invention provides a compound of formula I (including a stable isotope substitute thereof) or a pharmaceutically acceptable salt thereof, a compound of formula II (including a stable isotope substitute thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination of the present invention
  • Preparations are used to treat conditions mediated by FGFR-4, conditions characterized by FGFR-4 overexpression, conditions characterized by FGFR4 amplification, conditions mediated by FGF19, and characteristics characterized by amplified FGF19.
  • Alkyl refers to a monovalent group of a saturated straight or branched hydrocarbon, such as a straight or branched chain of 1-6, 1-4, or 1-3 carbon atoms.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl , 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1 -Pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl 1-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopen
  • the alkyl group is understood as a C1-6 alkyl group.
  • C 0 alkyl in C 0-3 alkyl refers to a chemical bond.
  • Alkenyl refers to an aliphatic group containing at least one double bond.
  • alkynyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and is characterized by having one or more triple bonds.
  • alkynyl include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
  • One of the triple bond carbons may optionally be a point of attachment for an alkynyl substituent.
  • amplification means generating additional copies of a gene or chromosomal fragment in a cancer cell that may confer a growth or survival advantage.
  • aryl or a synonym (such as an aromatic ring) refers to 5-, 6-, and 7-membered monocyclic aromatic groups that can include 0 to 4 heteroatoms, such as furan, pyrrole, Thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “arylheterocycles" or “heteroaromatic groups”.
  • Aromatic rings may be substituted at one or more ring positions with substituents such as those described above (e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, polycyclic, Hydroxyl, alkoxy, amino, nitro, mercapto, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl , Sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN or similar groups).
  • substituents such as those described above (e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, polycyclic, Hydroxyl, alkoxy, amino, nitro, mercapto
  • Any substitutable ring atom may be substituted (eg, substituted with one or more substituents).
  • Covalent inhibitor as used herein means an inhibitor that can form a covalent bond with a protein.
  • FGFR-4" or "FGFR-4 protein” refers to any form of FGFR-4 protein, including wild-type and all variant forms (including, without limitation, mutant forms and splice variants).
  • the FGFR-4 protein is a product of the FGFR-4 gene, and as such the FGFR-4 protein includes any form of the FGFR-4 gene (including all aberrations such as point mutations, insertions / deletions, translocation fusions, and focal amplification ) Any protein encoded.
  • inhibitor refers to a compound that inhibits an enzyme such that, for example, a decrease in enzyme activity can be observed in a biochemical assay.
  • the inhibitor has an IC50 of less than about 1 ⁇ M, less than about 500 nM, less than about 250 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM.
  • FGFR-4 inhibitor refers to a compound that inhibits FGFR-4.
  • “Overexpression” as used herein means that the yield of a gene product in a sample is significantly higher than that observed in a control sample population (e.g., normal tissue).
  • Selectivity means that a compound inhibits the activity of a target protein (eg, FGFR-4) more effectively than it inhibits the activity of other proteins.
  • a target protein eg, FGFR-4
  • the isotypes FGFR-1, FGFR-2, FGFR-3 and FGFR-4 are all considered different proteins.
  • a compound can inhibit the activity of a target protein (e.g., FGFR-4) at least 1.5 times, at least 2 times, at least 5 times, at least 10 times, at least 20 times, more effectively than its activity at inhibiting non-target proteins, At least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, at least 200 times, at least 500 times, or at least 1000 times or more.
  • a target protein e.g., FGFR-4
  • substitution refers herein to a moiety where a hydrogen on one or more carbons of the main chain is replaced by a substituent. It should be understood that “substitution” or “substituted by” includes the implicit condition that such substitutions are in accordance with the allowable valences of substituted atoms and substituents, and that substitutions result in stable compounds, for example, which do not undergo spontaneous transformation, such as by Rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is intended to include all permissible substituents of organic compounds.
  • permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents may be one or more and the same or different.
  • heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valence of the heteroatoms.
  • Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thio) (Formate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, fluorenyl, imino, cyano, nitro, azide, thiol , Alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moiety.
  • substituents described herein for example, halogen, hydroxyl, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl
  • substituted portion on the hydrocarbon chain may itself be substituted as needed.
  • the substituents of substituted alkyl may include substituted and unsubstituted amino, azido, imino, amido, phosphoryl (including phosphonate and phosphonate), sulfonyl ( (Including sulfate, sulfonamide, sulfamoyl and sulfonate) and silyl, and ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF3, -CN, etc. . Exemplary substituted alkyl groups are described below.
  • the cycloalkyl group may be further substituted with an alkyl group, an alkenyl group, an alkoxy group, an alkylthio group, an aminoalkyl group, an alkyl group substituted with a carbonyl group, -CF3, -CN, or the like.
  • Alkenyl and alkynyl can be similarly substituted to produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, Alkenyl or alkynyl substituted with carbonyl.
  • the definition of each expression e.g., alkyl, m, n, etc.
  • sulfonyl refers to -SO2-.
  • sulfonamido refers to -S (O) -N (R1) (R 2 ) or -N (R1) -S (O) -R 2 , wherein R 1 and R 2 are each independently H Or alkyl.
  • the compounds described herein may contain atomic isotopes in unnatural proportions at one or more of the atoms constituting such compounds.
  • compounds can be radiolabeled with a radioisotope, such as, for example, tritium ( 3 H) or carbon-14 ( 14 C). All isotopic variations, whether radioactive or not, of the compounds disclosed herein are intended to be encompassed within the scope of the invention.
  • deuterated compounds or compounds containing 13 C are intended to be included within the scope of the present invention.
  • compositions may exist in different tautomeric forms, and all possible tautomeric forms of all compounds described herein are intended to be encompassed within the scope of the present invention.
  • the "enantiomeric excess" or "% enantiomeric excess” of the composition can be calculated using the formula shown below. In the examples shown below, the composition contains 90% of one enantiomer (e.g., S-enantiomer) and 10% of the other enantiomer (i.e., R-enantiomer) Conformation).
  • compositions containing 90% of one enantiomer and 10% of the other enantiomer is said to have an 80% enantiomeric excess.
  • Some of the compositions described herein contain an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the compound (S-enantiomer ).
  • the composition contains an S-enantiomer in an enantiomeric excess compared to the R-enantiomer.
  • the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations ( For each asymmetric center), Z and E double bond isomers, and Z and E conformation isomers.
  • isomeric e.g., enantiomeric, diastereomeric, and geometric (or conformational)
  • R and S configurations For each asymmetric center
  • Z and E double bond isomers For each asymmetric center
  • Z and E double bond isomers For each asymmetric center
  • Z and E double bond isomers Z and E conformation isomers
  • single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention.
  • all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds described herein can be used as a free base or as a salt.
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate , Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate, glucose Heptanoate, lactobate and laurylsulfonate.
  • a salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate , Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate, glucose
  • solvated forms may exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention.
  • Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms.
  • compositions disclosed herein can be administered alone, the compounds are preferably administered as a pharmaceutical formulation, wherein the compound is combined with one or more pharmaceutically acceptable excipients or carriers.
  • the compounds disclosed herein can be formulated for administration in any convenient manner for use in human or veterinary medicine.
  • the compound included in the pharmaceutical formulation may be active by itself, or may be, for example, a prodrug capable of being converted into the active compound in a physiological environment.
  • compounds provided herein include hydrates thereof.
  • the phrase "pharmaceutically acceptable” means that it is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications within reasonable medical judgment, and is equivalent to a reasonable benefit / risk ratio Those compounds, substances, compositions and / or dosage forms.
  • Examples of pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • Suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate , Fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodate, lactate, maleate, malonate , Mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfuric acid Salt, tartrate, tosylate, and undecanoate.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) salts, ammonium and N - (alkyl) 4 + salts.
  • alkali metal e.g. sodium
  • alkaline earth metal e.g. magnesium
  • ammonium e.g. sodium
  • N - (alkyl) 4 + salts e.g. sodium
  • alkali metal e.g. sodium
  • alkaline earth metal e.g. magnesium
  • ammonium e.g. sodium
  • Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, Mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc .; (2) oil-soluble antioxidants , Such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, etc .; and (3) metal chelating agents such as Citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc .
  • oil-soluble antioxidants Such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lec
  • Solid dosage forms may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or Any of: (1) bulking or bulking agents such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethyl cellulose, alginate , Gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates And sodium carbonate; (5) solution blockers, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glyceryl monostea
  • Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • liquid dosage forms may contain inert diluents (such as, for example, water or other solvents), solubilizers, and emulsifiers (such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol Fatty acid esters of alcohols and sorbitan, and mixtures thereof.
  • inert diluents such as, for example, water or other solvents
  • solubilizers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3
  • the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth , And mixtures thereof.
  • suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth , And mixtures thereof.
  • ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols , Silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.
  • powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or a mixture of these materials.
  • Sprays may additionally contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons (such as butane and propane).
  • propellants such as chlorofluorocarbons
  • volatile unsubstituted hydrocarbons such as butane and propane
  • formulations are conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical arts.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host to be treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount that the compound produces a therapeutic effect.
  • Dosage forms of the compounds of this invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.
  • a compound disclosed herein When a compound disclosed herein is administered to humans and animals as a medicament, it can be used by itself or as an active ingredient containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) and a pharmaceutically acceptable carrier.
  • the combined pharmaceutical composition is administered.
  • the formulation can be topical, oral, transdermal, rectal, vaginal, parentally, intranasal, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, peritoneal Administration is intradermal, subcutaneous, subcutaneous, or by inhalation.
  • FGFR-4 regulates proliferation, survival, and alpha-fetoprotein secretion during the progression of hepatocellular carcinoma (HCC); FGFR-4 inhibitors are therefore promising potential therapeutic agents for this unmet medical need (Ho et al., Journal of Hepatology, 2009, 50: 118-27).
  • HCC afflicts more than 550,000 people worldwide each year and is one of the worst 1-year survival rates of any cancer type. Additional evidence for the link between FGFR-4 and HCC is shown through the involvement of FGF19 (a member of the fibroblast growth factor (FGF) family, which consists of hormones) in regulating blood glucose, blood lipids, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have been observed in FGF19 gene transgenic mice. FGF19 activates FGFR-4 (its main receptor in the liver), and FGFR-4 activation is considered to be a mechanism by which FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation (Wu et al., J.
  • FGF19 a member of the fibroblast growth factor (FGF) family, which consists of hormones) in regulating blood glucose, blood lipids, and energy homeostasis.
  • FGF19 activates FGFR-4 (its main receptor in the liver), and FGFR-4 activation is
  • FGF19 has also been identified as a driver gene in HCC (Sawey et al. Cancer Cell (2011) 19: 347-358). Therefore, the compounds disclosed herein, which are potential and selective inhibitors of FGFR-4, are believed to be useful in the treatment of HCC and other liver cancers.
  • Tumor genome screening has identified an activated fibroblast growth factor receptor 4 (FGFR-4) Y367C mutation in the human breast cancer cell line MDA-MB-453. Therefore, it has been suggested that FGFR-4 may be a driver of tumor growth in breast cancer (Roidl et al., Oncogene (2010) 29 (10): 1543-1552).
  • the compounds disclosed herein which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated breast cancer.
  • Molecular changes eg, translocations
  • PAX3-FKHR translocation / gene fusion can cause FGFR-4 overexpression.
  • FGFR-4 overexpression due to this mechanism is associated with rhabdomyosarcoma (RMS) (Cao et al. Cancer Res (2010) 70 (16): 6497-6508).
  • RMS rhabdomyosarcoma
  • Mutations in FGFR-4 itself can lead to protein overactivation; this mechanism has been associated with the RMS subpopulation (Taylor et al., J. Clin Invest (2009) 119: 3395-3407). Therefore, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated RMS and other sarcomas. Other diseases are associated with changes in genes upstream of FGFR-4 or with mutations in FGFR-4 itself.
  • FGFR-4 mutations in the kinase domain of FGFR-4 result in over-activation, which is associated with lung adenocarcinoma (Ding et al., Nature (2008) 455 (7216): 1069-1075).
  • FGFR-4 amplification is associated with conditions such as renal cell carcinoma (TCGA provisional data).
  • silencing FGFR4 and inhibiting ligand-receptor binding significantly slowed ovarian tumor growth, suggesting that inhibitors of FGFR4 can be used to treat ovarian cancer.
  • the pathogenic increase in bile acid levels is associated with changes in FGF19 levels (Vergnes et al., Cell Metabolism (2013) 17,916-28). Therefore, reduced levels of FGF19 may have benefits in promoting the synthesis of bile acids and therefore in the treatment of hyperlipidemia.
  • the dosage level may alter the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, composition, and mode of administration of a particular patient and is non-toxic to the patient.
  • the selected dosage level will depend on a number of factors, including the activity of the specific compound or its ester, salt or amide used herein, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, and the combination with the specific compound used
  • Other drugs, compounds and / or substances used age, sex, weight, condition, general health and previous medical history of patients to be treated, and similar factors well known in the medical field. A physician or veterinarian in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a physician or veterinarian can begin the administration of a compound of the invention for use in a pharmaceutical composition at a level below the required dose to achieve the desired effect and gradually increase the dose until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. This effective dose will usually depend on the factors described above.
  • the dosage of a compound of the invention for use in a patient will be from about 0.0001 mg to about 100 mg per kilogram of body weight per day.
  • the dose may be between 10 mg and 2000 mg per day.
  • the dose may be between 100 mg and 1000 mg per day, or between 200 mg and 600 mg per day.
  • the effective daily dose of the active compound may be administered as one, two, three, four or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.
  • the FGFR-4 inhibitors disclosed herein can be administered in combination with other cancer treatments.
  • the inhibitor may be administered in combination with surgical treatment, radiation or other therapeutic agents (such as antibodies), other selective kinase inhibitors, or chemotherapeutic agents.
  • the inhibitor may also be administered in combination with RNAi therapy or antisense therapy.
  • the FGFR-4 inhibitors described herein can be combined with one, two, or more other therapeutic agents.
  • the "second therapeutic agent" also includes more than one therapeutic agent other than the FGFR-4 inhibitor.
  • the compounds disclosed herein can be combined with agents such as sorafenib.
  • the FGFR-4 inhibitors described herein can be administered with one, two, or more other therapeutic agents.
  • the FGFR-4 inhibitor and the second therapeutic agent described herein need not be administered in the same pharmaceutical composition, and may be administered by different routes due to different physical and chemical properties.
  • the FGFR-4 inhibitor can be administered orally, while the second therapeutic agent is administered intravenously.
  • the determination of the mode of administration and the rationality of administration is entirely within the knowledge of the skilled clinician. Initial administration can be performed according to established protocols known in the art, and then the skilled clinician can change the dosage, mode of administration, and time of administration based on the observed effects.
  • the FGFR-4 inhibitor and the second therapeutic agent may be administered simultaneously (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially (i.e., one after the other, at any time interval therebetween), depending on proliferation
  • FGFR-4 inhibitors disclosed herein can be administered as part of an antibody-drug conjugate, where the FGFR-4 inhibitor is the "payload" portion of the conjugate.
  • the compounds of the invention can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic pathways, such as those in the schemes below.
  • the reaction for preparing the compound of the present invention can be performed in a suitable solvent, and those skilled in the art of organic synthesis can easily select a solvent.
  • Suitable solvents may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is performed (eg, a temperature in the range of the solvent freezing temperature to the solvent boiling temperature).
  • a given reaction may be performed in one solvent or a mixture of more than one solvent.
  • the skilled person can select a solvent suitable for a specific reaction step depending on the specific reaction step.
  • the preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the selection of an appropriate protecting group.
  • the chemical nature of the protecting group can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • the reaction can be monitored according to any suitable method known in the art.
  • spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry (MS)), or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.
  • NMR nuclear magnetic resonance
  • IR infrared
  • spectrophotometry e.g., UV-visible light
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the reagents used herein are all commercially available products without purification.
  • the solvents were re-distilled before use.
  • the reaction was monitored by a thin layer silica gel plate (TLC, GF254, 60-F250, 0.2mm, Yantai Jiangyou Silica Gel Thin Layer Chromatography).
  • NMR was measured using Bruker Advance 400 (1H: 400MHz; 13C: 100MHz) or Bruker Advance 500 (1H: 500MHz; 13C: 125MHz) nuclear magnetic resonance instrument, with TMS as the internal standard.
  • High-resolution mass spectrometry using ABI Q-star Elite high-resolution mass spectrometer; final product purity detection using high-performance liquid phase (HPLC)
  • HPLC high-performance liquid phase
  • Agilent 1260 series chromatography Agilent 1260 series chromatography (Agilent PN959990-902Eclipse Plus C18 (250mm ⁇ 4.6mm) column) The wavelength is 254 nm.
  • reaction was monitored by TLC for complete reaction, diluted with water (10 mL), and extracted with ethyl acetate (3 ⁇ 10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.14 g of a colorless oily liquid with a yield of 95%.
  • reaction solution was concentrated and extracted by adding water (20 mL) and ethyl acetate (3 ⁇ 20 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 100 mg of a yellow solid. Yield 21%.
  • reaction solution was stirred at 100 ° C overnight, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 x 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.045 g of a yellow solid with a yield of 48%.
  • reaction solution was stirred at 110 ° C. for 6 h, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 ⁇ 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.16 g of a yellow solid with a yield of 69%.
  • reaction solution was concentrated and extracted by adding water (20 mL) and ethyl acetate (3 ⁇ 20 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 39 mg of a yellow solid. Yield: 43%.
  • reaction solution was stirred overnight at 100 ° C, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 x 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.15 g of a yellow solid with a yield of 62%.
  • Detection steps adding a 1: 1 mixture of Eu 3+ chelating antibody (5 ⁇ L) and streptavidin-XL665 (0.125 ⁇ M, 5 ⁇ L) in advance to stop the reaction. After standing at room temperature for 1 hour, read the plate on a PE Envision microplate reader. Using the concentration as the abscissa and the signal value of 615nm / 665nm as the ordinate, the curve was fitted with GraphPad Prism 5.0, and the IC 50 value was calculated.
  • HUH-7 cells (Shanghai Cell Bank of the Chinese Academy of Sciences), MDA-MB-453 cells (Shanghai Cell Bank of the Chinese Academy of Sciences), DMEM medium (11995065, Gibco), Leibovitz's L-15 medium (11415064, Gibco), detection reagents (G7570, Promega).
  • the 96-well plate was allowed to stand at room temperature for 0.5h, and the detection reagent (40 ⁇ L) was added. After thorough mixing, the plate was allowed to stand for 1h. The plate was read on a microplate reader and the DMSO well signal was used as a positive control to calculate the growth inhibition rate. GraphPad Prism 5.0 was used to fit the logarithm of the inhibitory rate to the inhibitor concentration, and the cell EC 50 values were calculated.
  • the compound 1-22 of the present invention has a good inhibitory effect on cell proliferation.
  • the results of some compounds in the cell lines HuH-7 and MDA-MB-453 are as follows.
  • Staurosporine (astrosporine, non-covalent inhibitor, 250nM), compound 11 (40nM) and kinase buffer (positive control) were incubated with FGFR4 kinase at different times (0, 1min, 2min, 4min, 8min, 16min, 30min, 45min ) After adding ATP (120 ⁇ M) and substrate (1 ⁇ M) 1: 1 mixture (4 ⁇ L) to start the enzymatic reaction. Incubate for 45min at 25 ° C after shaking and centrifugation. The reaction was stopped by adding a previously mixed 1: 1 Eu 3+ chelating antibody (5 ⁇ L) and streptavidin-XL665 (0.125 ⁇ M, 5 ⁇ L).
  • the ratio of each time point to the positive control signal was used to calculate the inhibition rate ((1-signal sample / signal control ) ⁇ 100%), and GraphPad Prism 5.0 was used to fit the inhibition rate against time to obtain a time-dependent inhibition curve.
  • the inhibitory activity of compound 11 on FGFR4 increased as the co-incubation time of compound 11 and FGFR4 kinase increased; but the inhibitory intensity of non-covalent inhibitor Staurosporine on FGFR4 did not change with the co-incubation time.

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Abstract

Disclosed are a kinase selective inhibitor, a pharmaceutical composition comprising the same, and medical use thereof.

Description

一种激酶选择性抑制剂Kinase selective inhibitor 技术领域Technical field
本发明涉及一种激酶选择性抑制剂，包含其的药物组合物，以及其的医药用途。The invention relates to a kinase selective inhibitor, a pharmaceutical composition comprising the same, and a medicinal use thereof.
背景技术Background technique
成纤维细胞生长因子受体4(FGFR-4)是人体内由FGFR-4基因编码的蛋白质。此种蛋白质是纤维母细胞生长因子受体家族成员，其中在整个进化过程中各成员间的氨基酸序列高度保守。FGFR家族成员1-4彼此有不同的配体亲和力和组织分布。全长代表性蛋白质的组成为由三个疫球蛋白样结构域组成的胞外区域、单个疏水性跨膜区段和细胞质酪氨酸激酶结构域。蛋白质的胞外部分与纤维母细胞生长因子相互作用，引发下游信号级联，最终影响有丝分裂和分化。FGFR-4基因的基因组组织包括18个外显子。尽管已观察到选择性剪接，但没有证据表明此种蛋白质C端的一半IgIII结构域在另三种形式(所指为FGFR1-3)之间不同。Fibroblast growth factor receptor 4 (FGFR-4) is a protein encoded by the FGFR-4 gene in humans. This protein is a member of the fibroblast growth factor receptor family, in which the amino acid sequence is highly conserved among members throughout the evolution process. FGFR family members 1-4 have different ligand affinities and tissue distributions from each other. The composition of the full-length representative protein is an extracellular region composed of three epiglobin-like domains, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain. The extracellular part of the protein interacts with fibroblast growth factor, triggering a downstream signaling cascade, and ultimately affecting mitosis and differentiation. The genomic organization of the FGFR-4 gene includes 18 exons. Although alternative splicing has been observed, there is no evidence that the half-IgIII domain of the C-terminus of such proteins differs between the other three forms (referred to as FGFR1-3).
发明内容Summary of the Invention
本发明描述了FGFR-4的抑制剂。本发明还描述了包含FGFR-4抑制剂的药物制剂。The invention describes inhibitors of FGFR-4. The invention also describes pharmaceutical formulations comprising FGFR-4 inhibitors.
具体来说，本发明提供了下述技术方案：Specifically, the present invention provides the following technical solutions:
技术方案1.一种式(I)所示的化合物、其盐或其立体异构体Technical Solution 1. A compound represented by formula (I), a salt thereof, or a stereoisomer thereof
Figure PCTCN2019090131-appb-000001
Figure PCTCN2019090131-appb-000001
G 1和G 2彼此独立地，相同地或不同地，选自H，C(O)和S(O) 2； G 1 and G 2 are independently, identically or differently selected from H, C (O) and S (O) 2 ;
L 1和L 2彼此独立地，相同地或不同地，选自任选地被C 1-3烷基取代的C 2-3烯基、C 0-3烷基-C 2-3烯基和C 1-3烷基-NHC(O)-C 2-3烯基； L 1 and L 2 are independently of each other, identically or differently, selected from C 2-3 alkenyl, C 0-3 alkyl-C 2-3 alkenyl, and optionally substituted with C 1-3 alkyl C 1-3 alkyl-NHC (O) -C 2-3 alkenyl;
前提是当G 1为H时，L 1不存在，以及当G 2为H时，L 2不存在。 The premise is that when G 1 is H, L 1 does not exist, and when G 2 is H, L 2 does not exist.
其中，among them,
Ar是5或6元单环芳香环，Ar is a 5- or 6-membered monocyclic aromatic ring,
例如：呋喃、吡咯、噻吩、咪唑、吡唑、噁唑、异噁唑、噻唑、苯、吡啶、吡嗪、嘧啶、哒嗪、三唑，For example: furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole,
优选：苯、吡啶；Preferred: benzene, pyridine;
R 1 R 1
选自H、卤素(优选-Cl),-OH,-C 1-4烷基,-C 1-4烷基氧基,
Figure PCTCN2019090131-appb-000002
Figure PCTCN2019090131-appb-000003
Selected from H, halogen (preferably -Cl), -OH, -C 1-4 alkyl, -C 1-4 alkyloxy,
Figure PCTCN2019090131-appb-000002
Figure PCTCN2019090131-appb-000003
m是0，1，2，3，4，5的整数；m is an integer of 0,1,2,3,4,5;
W 1是CH,CR 1或N； W 1 is CH, CR 1 or N;
W 2是CH,CR 1或N； W 2 is CH, CR 1 or N;
W 3是CH,CR 1或N； W 3 is CH, CR 1 or N;
W 4是CH,CR 1或N； W 4 is CH, CR 1 or N;
W 5是CH,CR 1或N； W 5 is CH, CR 1 or N;
W 6是CH,CR 1或N； W 6 is CH, CR 1 or N;
W 7是CH,CR 1或N； W 7 is CH, CR 1 or N;
L选自：键,-O-,-NH-,-S-,-CH 2-,-CH＝CH-,-CH≡CH-,-C(CH 3)H-,-C(CH 3) 2-,-C(CH 2-CH 2)-,-CClH-,-CCl 2-,-CO-,-SO-,和-SO 2-； L is selected from: bond, -O-, -NH-, -S-, -CH 2- , -CH = CH-, -CH≡CH-, -C (CH 3 ) H-,-C (CH 3 ) 2 -,-C (CH 2 -CH 2 )-,-CClH-,-CCl 2 -,-CO-,-SO-, and -SO 2- ;
n是0，1，2，3，4，5的整数；n is an integer of 0,1,2,3,4,5;
R 2 R 2
选自H、卤素(优选-Cl),-OH,-C 1-4烷基,-C 1-4烷基氧基,
Figure PCTCN2019090131-appb-000004
Figure PCTCN2019090131-appb-000005
Selected from H, halogen (preferably -Cl), -OH, -C 1-4 alkyl, -C 1-4 alkyloxy,
Figure PCTCN2019090131-appb-000004
Figure PCTCN2019090131-appb-000005
R 3选自H、-C 1-4烷基。 R 3 is selected from H and -C 1-4 alkyl.
技术方案2.前述技术方案中任一项的化合物、其盐或其立体异构体，Technical solution 2. The compound according to any one of the foregoing technical solutions, a salt thereof, or a stereoisomer thereof,
其中，G 2是H，L 2不存在。 Among them, G 2 is H, and L 2 does not exist.
技术方案3.前述技术方案中任一项的化合物、其盐或其立体异构体，Technical solution 3. The compound according to any one of the foregoing technical solutions, a salt thereof, or a stereoisomer thereof,
其中W 1,W 2,W 3,W 4,W 5,W 6,W 7都是CH。 W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , and W 7 are all CH.
技术方案4.前述技术方案中任一项的化合物、其盐或其立体异构体，Embodiment 4. The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof,
其中R 3是H。 Where R 3 is H.
技术方案5.前述技术方案中任一项的化合物、其盐或其立体异构体，Technical solution 5. The compound according to any one of the foregoing technical solutions, a salt thereof, or a stereoisomer thereof,
其中-N(G 1L 1)(G 2L 2)是-NH-CO-C 2-3烯基。 Where -N (G 1 L 1 ) (G 2 L 2 ) is -NH-CO-C 2-3 alkenyl.
技术方案6.前述技术方案中任一项的化合物、其盐或其立体异构体，Technical solution 6. The compound according to any one of the foregoing technical solutions, a salt thereof, or a stereoisomer thereof,
其中Ar是苯基。Where Ar is phenyl.
技术方案7.前述技术方案中任一项的化合物、其盐或其立体异构体，Embodiment 7. The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof,
其中L是
Figure PCTCN2019090131-appb-000006
Where L is
Figure PCTCN2019090131-appb-000006
技术方案8.前述技术方案中任一项的化合物、其盐或其立体异构体，Ar或Ar-(R 1) m是
Figure PCTCN2019090131-appb-000007
Embodiment 8. The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, Ar or Ar- (R 1 ) m is
Figure PCTCN2019090131-appb-000007
技术方案9.前述技术方案中任一项的化合物、其盐或其立体异构体，Ar或Ar-(R 1) m是
Figure PCTCN2019090131-appb-000008
Embodiment 9. The compound, salt or stereoisomer thereof according to any one of the foregoing embodiments, Ar or Ar- (R 1 ) m is
Figure PCTCN2019090131-appb-000008
技术方案10.前述技术方案中任一项的化合物、其盐或其立体异构体，Ar或Ar-(R 1) m是
Figure PCTCN2019090131-appb-000009
 Embodiment 10. The compound according to any one of the foregoing embodiments, a salt thereof or a stereoisomer thereof, Ar or Ar- (R 1 ) m is
Figure PCTCN2019090131-appb-000009
技术方案11.前述技术方案中任一项的化合物、其盐或其立体 异构体，Ar或Ar-(R 1) m是
Figure PCTCN2019090131-appb-000010
Embodiment 11. The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, Ar or Ar- (R 1 ) m is
Figure PCTCN2019090131-appb-000010
技术方案12.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是H。 Embodiment 12. The compound according to any one of the preceding embodiments, a salt thereof or a stereoisomer thereof, and R 2 or (R 2 ) n is H.
技术方案13.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是
Figure PCTCN2019090131-appb-000011
Embodiment 13. The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, and R 2 or (R 2 ) n is
Figure PCTCN2019090131-appb-000011
技术方案14.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是
Figure PCTCN2019090131-appb-000012
Embodiment 14. The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, and R 2 or (R 2 ) n is
Figure PCTCN2019090131-appb-000012
技术方案15.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是
Figure PCTCN2019090131-appb-000013
Embodiment 15. The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
Figure PCTCN2019090131-appb-000013
技术方案16.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是
Figure PCTCN2019090131-appb-000014
Embodiment 16. The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
Figure PCTCN2019090131-appb-000014
技术方案17.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是
Figure PCTCN2019090131-appb-000015
Embodiment 17. The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
Figure PCTCN2019090131-appb-000015
技术方案18.前述技术方案中任一项的化合物、其盐或其立体异构体，R 2或(R 2) n是
Figure PCTCN2019090131-appb-000016
Embodiment 18. The compound according to any one of the preceding embodiments, a salt thereof, or a stereoisomer thereof, R 2 or (R 2 ) n is
Figure PCTCN2019090131-appb-000016
技术方案19.一种化合物、其盐或其立体异构体，其中所述化合物选自下述化合物1-23：Embodiment 19. A compound, a salt thereof or a stereoisomer thereof, wherein the compound is selected from the following compounds 1-23:
Figure PCTCN2019090131-appb-000017
Figure PCTCN2019090131-appb-000017
Figure PCTCN2019090131-appb-000018
Figure PCTCN2019090131-appb-000018
Figure PCTCN2019090131-appb-000019
Figure PCTCN2019090131-appb-000019
Figure PCTCN2019090131-appb-000020
Figure PCTCN2019090131-appb-000020
技术方案20.一种药物组合物，其包括前述技术方案中任一项所述的化合物、其盐或其立体异构体，和药学上可接受的载体。 Embodiment 20. A pharmaceutical composition comprising the compound according to any one of the preceding embodiments, a salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
技术方案21.前述技术方案中任一项所述的化合物、其盐或其立体异构体，或前述技术方案中任一项所述的药物组合物在制备用于治疗由FGFR-4介导的病状、以FGFR-4过表达为特征的病状、以FGFR4扩增为特征的病状、由FGF19介导的病状、以扩增的FGF19为特征的病状或以FGF19过表达为特征的病状的药物中的用途。Embodiment 21. The compound according to any one of the foregoing embodiments, a salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to any one of the foregoing embodiments, is prepared for treatment by FGFR-4. Pathological conditions, conditions characterized by FGFR-4 overexpression, conditions characterized by FGFR4 amplification, conditions mediated by FGF19, conditions characterized by amplified FGF19, or conditions characterized by FGF19 overexpression Use.
技术方案22.前述技术方案中任一项所述的用途，其中所述病状是肝细胞癌、乳腺癌、卵巢癌、肺癌、肝癌、肉瘤或高脂血症。Technical solution 22. The use according to any one of the preceding technical solutions, wherein the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma or hyperlipidemia.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1说明了“时间依赖性抑制实验”的结果。Figure 1 illustrates the results of the "time-dependent inhibition experiment".
具体实施方式Detailed ways
在一个方面中，本发明提供了一种上述式(I)所示的化合物(包括其稳定同位素替代物)、其盐或其立体异构体，其是一种FGFR-4选择性抑制剂。In one aspect, the present invention provides a compound represented by the above formula (I) (including a stable isotope substitute thereof), a salt thereof, or a stereoisomer thereof, which is a FGFR-4 selective inhibitor.
在一个方面中，本发明提供了一种药物组合物，其包括式I化合物(包括其稳定同位素替代物)或其药学上可接受的盐、或式II化合物(包括其稳定同位素替代物)或其药学上可接受的盐，和药学上可接受的载体。药学上可接受性载体包括惰性固体填充剂或者赋形剂 以及无菌水溶液或者有机溶液。所述化合物应当以足以提供期望的药剂剂量的量存在于所述的药物组合物中。配制并且施用本发明中公开的化合物的技术是本领域技术人员公知的，例如可以在Remington：the Science and Practice of Pharmacy《雷明顿药物科学与实践》，第19版，Mack出版公司，Easton，PA(1995年)中找到。In one aspect, the invention provides a pharmaceutical composition comprising a compound of formula I (including a stable isotope replacement thereof) or a pharmaceutically acceptable salt thereof, or a compound of formula II (including a stable isotope replacement thereof) or Its pharmaceutically acceptable salts, and pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers include inert solid fillers or excipients and sterile aqueous or organic solutions. The compound should be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage of the agent. Techniques for formulating and administering the compounds disclosed in the present invention are well known to those skilled in the art, and can be found, for example, in Remington: The Science and Practice of Pharmacy, Remington Pharmaceutical Science and Practice, 19th Edition, Mack Publishing Company, Easton, PA (1995).
本发明提供了式I化合物(包括其稳定同位素替代物)或其药学上可接受的盐、式II化合物(包括其稳定同位素替代物)或其药学上可接受的盐、或者本发明的药物组合物在制备用于治疗由FGFR-4介导的病状、以FGFR-4过表达为特征的病状、以FGFR4扩增为特征的病状、由FGF19介导的病状、以扩增的FGF19为特征的病状或以FGF19过表达为特征的病状的药物中的用途；特别地所述病状是肝细胞癌、乳腺癌、卵巢癌、肺癌、肝癌、肉瘤或高脂血症。The present invention provides a compound of formula I (including a stable isotope substitute thereof) or a pharmaceutically acceptable salt thereof, a compound of formula II (including a stable isotope substitute thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination of the present invention Preparations are used to treat conditions mediated by FGFR-4, conditions characterized by FGFR-4 overexpression, conditions characterized by FGFR4 amplification, conditions mediated by FGF19, and characteristics characterized by amplified FGF19. Use of a condition or a medicament characterized by FGF19 overexpression; particularly the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma or hyperlipidemia.
如本文所用的“烷基”是指饱和直链或支链烃的单价基团，诸如1-6个、1-4个或1-3个碳原子的直链或支链基团。例示性烷基包括但不限于甲基、乙基、丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2，2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2，2-二甲基-1-丁基、3，3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基等。在本文中，如果没有规定烷基的碳原子数的上限和/或下限的话，该烷基按C1-6烷基理解。在本文中，例如C 0-3烷基中的C 0烷基是指一个化学键。 "Alkyl" as used herein refers to a monovalent group of a saturated straight or branched hydrocarbon, such as a straight or branched chain of 1-6, 1-4, or 1-3 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl , 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1 -Pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl 1-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl Base, hexyl, etc. In this context, if the upper and / or lower limit of the number of carbon atoms of an alkyl group is not specified, the alkyl group is understood as a C1-6 alkyl group. In this context, for example, C 0 alkyl in C 0-3 alkyl refers to a chemical bond.
如本文所用的“烯基”是指含有至少一个双键的脂族基团。"Alkenyl" as used herein refers to an aliphatic group containing at least one double bond.
如本文所用的“炔基”是指含有2-12个碳原子的直链或支链烃链且特征在于具有一个或多个三键。炔基的实例包括但不限于乙炔基、炔丙基和3-己炔基。三键碳中的一个可任选为炔基取代基的连接点。As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and is characterized by having one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be a point of attachment for an alkynyl substituent.
如本文所用的“扩增”意指在癌细胞中产生可能赋予生长或存活优势的基因或染色体片段的额外拷贝。As used herein, "amplification" means generating additional copies of a gene or chromosomal fragment in a cancer cell that may confer a growth or survival advantage.
如本文所用的“芳基”或同义术语(如芳香环)是指可包括0至4个杂原子的5-、6-和7-元单环芳族基团，例如，呋喃、吡咯、噻吩、咪唑、吡唑、噁唑、异噁唑、噻唑、苯、吡啶、吡嗪、嘧啶、哒嗪、三唑等。在环结构中具有杂原子的那些芳基还可称为“芳基杂环”或 “杂芳族基团”。芳族环可在一个或多个环位置处经诸如上文所述取代基(例如，卤素、叠氮基、烷基、芳烷基、烯基、炔基、环烷基、多环基、羟基、烷氧基、氨基、硝基、巯基、亚氨基、酰胺基、磷酸酯基、膦酸酯基、亚膦酸酯基、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、磺酰胺基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CF3、-CN或类似基团)取代。As used herein, "aryl" or a synonym (such as an aromatic ring) refers to 5-, 6-, and 7-membered monocyclic aromatic groups that can include 0 to 4 heteroatoms, such as furan, pyrrole, Thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "arylheterocycles" or "heteroaromatic groups". Aromatic rings may be substituted at one or more ring positions with substituents such as those described above (e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, polycyclic, Hydroxyl, alkoxy, amino, nitro, mercapto, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl , Sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN or similar groups).
如本文所用的“-C-(CH2-CH2)-”是指亚环丙基。"-C- (CH2-CH2)-" as used herein refers to cyclopropylidene.
任一可取代的环原子皆可经取代(例如，经一个或多个取代基取代)。Any substitutable ring atom may be substituted (eg, substituted with one or more substituents).
如本文所用的“共价抑制剂”意指可与蛋白质形成共价键的抑制剂。"Covalent inhibitor" as used herein means an inhibitor that can form a covalent bond with a protein.
“FGFR-4”或“FGFR-4蛋白”是指任何形式的FGFR-4蛋白，包括野生型和所有变体形式(包括不限于突变体形式和剪接变体)。FGFR-4蛋白是FGFR-4基因的产物，且因此FGFR-4蛋白包括由任何形式的FGFR-4基因(包括所有畸变，例如，点突变、插入/缺失、易位融合和局灶性扩增)编码的任何蛋白质。"FGFR-4" or "FGFR-4 protein" refers to any form of FGFR-4 protein, including wild-type and all variant forms (including, without limitation, mutant forms and splice variants). The FGFR-4 protein is a product of the FGFR-4 gene, and as such the FGFR-4 protein includes any form of the FGFR-4 gene (including all aberrations such as point mutations, insertions / deletions, translocation fusions, and focal amplification ) Any protein encoded.
如本文所用的“抑制剂”是指抑制酶而使(例如)在生物化学测定中可观察到到酶活性降低的化合物。As used herein, "inhibitor" refers to a compound that inhibits an enzyme such that, for example, a decrease in enzyme activity can be observed in a biochemical assay.
在某些实施方案中，抑制剂具有小于约1μM、小于约500nM、小于约250nM、小于约100nM、小于约50nM或小于约10nM的IC50。In certain embodiments, the inhibitor has an IC50 of less than about 1 μM, less than about 500 nM, less than about 250 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM.
FGFR-4抑制剂是指抑制FGFR-4的化合物。FGFR-4 inhibitor refers to a compound that inhibits FGFR-4.
如本文所用的“过表达”意指样品中基因产物的产量显著高于在对照样品群体(例如正常组织)中所观察到的产量。"Overexpression" as used herein means that the yield of a gene product in a sample is significantly higher than that observed in a control sample population (e.g., normal tissue).
“选择性”是指化合物抑制靶蛋白(例如，FGFR-4)的活性比其抑制其它蛋白质的活性更有效。在该情况中，同种型FGFR-1、FGFR-2、FGFR-3和FGFR-4全部被视为不同的蛋白质。"Selectivity" means that a compound inhibits the activity of a target protein (eg, FGFR-4) more effectively than it inhibits the activity of other proteins. In this case, the isotypes FGFR-1, FGFR-2, FGFR-3 and FGFR-4 are all considered different proteins.
在一些实施方案中，化合物可抑制靶蛋白(例如，FGFR-4)的活性比其抑制非靶蛋白的活性更有效至少1.5倍、至少2倍、至少5倍、至少10倍、至少20倍、至少30倍、至少40倍、至少50倍、至少60倍、至少70倍、至少80倍、至少90倍、至少100倍、至少200倍、至少500倍、或至少1000倍或更多倍。In some embodiments, a compound can inhibit the activity of a target protein (e.g., FGFR-4) at least 1.5 times, at least 2 times, at least 5 times, at least 10 times, at least 20 times, more effectively than its activity at inhibiting non-target proteins, At least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, at least 200 times, at least 500 times, or at least 1000 times or more.
无论前面是否冠以术语“任选”，“经取代”在本文中是指主链一个或多个碳上的氢由取代基替代的部分。应理解“取代”或“经……取代”包括隐含的条件为，此类取代是按照经取代原子和取代基的允许化合价，且取代产生稳定化合物，例如，其不自发进行转变，诸如通过重排、环化、消除等。如本文所用，预计术语“经取代”包括有机化合物所有可允许的取代基。在一个广泛方面，可允许的取代基包括有机化合物的非环状和环状、支链和无支链、碳环和杂环、芳族和非芳族取代基。对于适当有机化合物，可允许的取代基可为一个或多个且为相同的或不同的。出于本发明的目的，杂原子诸如氮可具有氢取代基和/或本文所述的有机化合物任何可允许的取代基，其满足杂原子的化合价。取代基可包括本文所述任何取代基，例如，卤素、羟基、羰基(诸如羧基、烷氧基羰基、甲酰基或酰基)、硫羰基(诸如硫酯基、硫代乙酸酯基或硫代甲酸酯基)、烷氧基、磷酰基、磷酸酯基、膦酸酯基、亚膦酸酯基、氨基、酰胺基、脒基、亚氨基、氰基、硝基、叠氮基、巯基、烷硫基、硫酸酯基、磺酸酯基、氨磺酰基、磺酰胺基、磺酰基、杂环基、芳烷基或芳族或杂芳族部分。本领域技术人员应理解，在烃链上经取代的部分自身可视需要经取代。例如，经取代烷基的取代基可包括经取代和未经取代形式的氨基、叠氮基、亚氨基、酰胺基、磷酰基(包括膦酸酯基和亚膦酸酯基)、磺酰基(包括硫酸酯基、磺酰胺基、氨磺酰基和磺酸酯基)和甲硅烷基、以及醚、烷硫基、羰基类(包括酮、醛、羧化物和酯)、-CF3、-CN等。下文描述例示性经取代烷基。环烷基可进一步经烷基、烯基、烷氧基、烷硫基、氨基烷基、经羰基取代的烷基、-CF3、-CN等取代。烯基和炔基可进行类似取代而产生(例如)氨基烯基、氨基炔基、酰胺基烯基、酰胺基炔基、亚氨基烯基、亚氨基炔基、硫烯基、硫炔基、经羰基取代的烯基或炔基。如本文所用，各表达(例如，烷基、m、n等)的定义在任何结构中出现不止一次时，意欲独立于其在同一结构中别处的定义。Whether or not preceded by the term "optional", "substituted" refers herein to a moiety where a hydrogen on one or more carbons of the main chain is replaced by a substituent. It should be understood that "substitution" or "substituted by" includes the implicit condition that such substitutions are in accordance with the allowable valences of substituted atoms and substituents, and that substitutions result in stable compounds, for example, which do not undergo spontaneous transformation, such as by Rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For a suitable organic compound, the permissible substituents may be one or more and the same or different. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valence of the heteroatoms. Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thio) (Formate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, fluorenyl, imino, cyano, nitro, azide, thiol , Alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moiety. Those skilled in the art will understand that the substituted portion on the hydrocarbon chain may itself be substituted as needed. For example, the substituents of substituted alkyl may include substituted and unsubstituted amino, azido, imino, amido, phosphoryl (including phosphonate and phosphonate), sulfonyl ( (Including sulfate, sulfonamide, sulfamoyl and sulfonate) and silyl, and ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF3, -CN, etc. . Exemplary substituted alkyl groups are described below. The cycloalkyl group may be further substituted with an alkyl group, an alkenyl group, an alkoxy group, an alkylthio group, an aminoalkyl group, an alkyl group substituted with a carbonyl group, -CF3, -CN, or the like. Alkenyl and alkynyl can be similarly substituted to produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, Alkenyl or alkynyl substituted with carbonyl. As used herein, the definition of each expression (e.g., alkyl, m, n, etc.), when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
如本文所用的“磺酰基”是指-SO2-。As used herein, "sulfonyl" refers to -SO2-.
如本文所用的“磺酰胺基”是指-S(O)-N(R1)(R 2)或-N(R1)-S(O)-R 2，其中R1和R 2各自独立地为H或烷基。 As used herein, "sulfonamido" refers to -S (O) -N (R1) (R 2 ) or -N (R1) -S (O) -R 2 , wherein R 1 and R 2 are each independently H Or alkyl.
本文所述化合物可在一个或多个构成此类化合物的原子处含有非天然比例的原子同位素。例如，化合物可用放射性同位素(诸如例 如氚( 3H)或碳-14( 14C))进行放射性标记。本文所公开化合物的所有同位素变化形式(无论是否具放射性)均意欲涵盖在本发明的范围内。例如，氘化化合物或含有 13C的化合物意欲涵盖在本发明的范围内。 The compounds described herein may contain atomic isotopes in unnatural proportions at one or more of the atoms constituting such compounds. For example, compounds can be radiolabeled with a radioisotope, such as, for example, tritium ( 3 H) or carbon-14 ( 14 C). All isotopic variations, whether radioactive or not, of the compounds disclosed herein are intended to be encompassed within the scope of the invention. For example, deuterated compounds or compounds containing 13 C are intended to be included within the scope of the present invention.
某些化合物可以不同互变异构形式存在，且所有本文所述化合物的所有可能的互变异构形式均意欲涵盖在本发明的范围内。组合物的“对映异构过量”或“对映异构过量％”可使用下文所示公式计算。在下文所示实施例中，组合物含有90％一种对映异构体(例如，S-对映异构体)和10％另一种对映异构体(即，R-对映异构体)。Certain compounds may exist in different tautomeric forms, and all possible tautomeric forms of all compounds described herein are intended to be encompassed within the scope of the present invention. The "enantiomeric excess" or "% enantiomeric excess" of the composition can be calculated using the formula shown below. In the examples shown below, the composition contains 90% of one enantiomer (e.g., S-enantiomer) and 10% of the other enantiomer (i.e., R-enantiomer) Conformation).
ee＝(90-10)/100＝80％。ee = (90-10) / 100 = 80%.
因此，含有90％一种对映异构体和10％另一种对映异构体的组合物称为具有80％对映异构过量。一些本文所述组合物含有对映异构过量为至少50％、至少75％、至少80％、至少85％、至少90％、至少95％或至少99％的化合物(S-对映异构体)。换句话说，所述组合物含有相比于R-对映异构体对映异构过量的S-对映异构体。Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an 80% enantiomeric excess. Some of the compositions described herein contain an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the compound (S-enantiomer ). In other words, the composition contains an S-enantiomer in an enantiomeric excess compared to the R-enantiomer.
除非另有说明，否则本文所绘示结构还意欲包括该结构的所有异构(例如，对映异构、非对映异构和几何(或构象))形式；例如，R和S构型(针对每个不对称中心而言)、Z和E双键异构体以及Z和E构象异构体。因此，本发明化合物的单一立体化学异构体以及对映异构、非对映异构和几何(或构象)混合物在本发明的范围内。除非另有说明，否则本发明化合物的所有互变异构形式均在本发明的范围内。Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations ( For each asymmetric center), Z and E double bond isomers, and Z and E conformation isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
本文所述化合物可作为游离碱或作为盐使用。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐和月桂基磺酸盐等。(参见，例如，Berge等人(1977)“Pharmaceutical Salts”，J.Pharm.Sci.66：1-19.)The compounds described herein can be used as a free base or as a salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate , Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate, glucose Heptanoate, lactobate and laurylsulfonate. (See, eg, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.)
本文所公开的某些化合物可以非溶剂化形式以及溶剂化形式(包括水合形式)存在。一般来说，溶剂化形式等效于非溶剂化形式且涵盖于本发明的范围内。Certain compounds disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention.
本文所公开的某些化合物可以多重结晶或非晶形形式存在。Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms.
一般来说，所有实体形式对于本发明所涵盖的用途均是等效的且意欲在本发明的范围内。In general, all physical forms are equivalent for the uses covered by the present invention and are intended to be within the scope of the present invention.
药物组合物Pharmaceutical composition
尽管本文所公开的合物能够单独施用，但所述化合物优选作为药物制剂施用，其中所述化合物与一种或多种药学上可接受的赋形剂或载体组合。Although the compositions disclosed herein can be administered alone, the compounds are preferably administered as a pharmaceutical formulation, wherein the compound is combined with one or more pharmaceutically acceptable excipients or carriers.
本文所公开化合物可经配制而以任何便利方式施用以用于人类或兽医医学。The compounds disclosed herein can be formulated for administration in any convenient manner for use in human or veterinary medicine.
在某些实施方案中，药物制剂中所包括的化合物自身可具活性，或可为例如能够在生理环境中转化成活性化合物的前药。In certain embodiments, the compound included in the pharmaceutical formulation may be active by itself, or may be, for example, a prodrug capable of being converted into the active compound in a physiological environment.
在某些实施方案中，本文所提供的化合物包括其水合物。In certain embodiments, compounds provided herein include hydrates thereof.
本文所用词组“药学上可接受”是指在合理医学判断范围内适合用于接触人类和动物的组织而无过度毒性、刺激、过敏反应或其它问题或并发症，与合理的益处/风险比相当的那些化合物、物质、组合物和/或剂型。As used herein, the phrase "pharmaceutically acceptable" means that it is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications within reasonable medical judgment, and is equivalent to a reasonable benefit / risk ratio Those compounds, substances, compositions and / or dosage forms.
本文所述化合物的药学上可接受的盐的实例包括从药学上可接受的无机和有机酸和碱衍生的那些。Examples of pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
适宜酸式盐的实例包括乙酸盐、己二酸盐、苯甲酸盐、苯磺酸盐、丁酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、甲酸盐、富马酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、棕榈酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和十一烷酸盐。Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate , Fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodate, lactate, maleate, malonate , Mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfuric acid Salt, tartrate, tosylate, and undecanoate.
从适当碱衍生的盐包括碱金属(例如钠)盐、碱土金属(例如镁)盐、铵盐和N -(烷基) 4 +盐。本发明还构思本文所述化合物的任何碱性含氮基团的季铵化。可通过此种季铵化获得水或油溶性或可分散产物。 Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) salts, ammonium and N - (alkyl) 4 + salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds described herein. Water or oil soluble or dispersible products can be obtained by such quaternization.
药学上可接受的载体的实例包括：(1)糖类，诸如乳糖、葡萄糖和蔗糖；(2)淀粉类，诸如玉米淀粉和马铃薯淀粉；(3)纤维素及其衍生物，诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；(4)粉状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，诸如可可脂和栓剂蜡；(9)油类，诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；(10)二醇类，诸如丙二醇；(11)多元醇，诸如甘油、山梨 醇、甘露醇和聚乙二醇；(12)酯类，诸如油酸乙酯和月桂酸乙酯；(13)琼脂；(14)缓冲剂，诸如氢氧化镁和氢氧化铝；(15)藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液；(19)乙醇；(20)磷酸盐缓冲溶液；(21)环糊精，和(22)用于药物制剂中的其它无毒相容物质，诸如基于聚合物的组合物。Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, Mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrin, and (22) for pharmaceutical preparations Other non-toxic compatible substances, such as polymer-based compositions.
药学上可接受的抗氧化剂的实例包括：(1)水溶性抗氧化剂，诸如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等；(2)油溶性抗氧化剂，诸如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等；和(3)金属螯合剂，诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc .; (2) oil-soluble antioxidants , Such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc .; and (3) metal chelating agents such as Citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.
固体剂型(例如，胶囊、片剂、丸剂、糖衣丸、散剂、颗粒剂等)可包括一种或多种药学上可接受的载体，诸如柠檬酸钠或磷酸二钙，和/或以下中的任一者：(1)填充剂或增量剂，诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸；(2)粘合剂，诸如，例如，羧甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和/或阿拉伯胶；(3)保湿剂，诸如甘油；(4)崩解剂，诸如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠；(5)溶液阻滞剂，诸如石蜡；(6)吸收促进剂，诸如季铵化合物；(7)润湿剂，诸如，例如，鲸蜡醇和甘油单硬脂酸酯；(8)吸附剂，诸如高岭土和膨润土；(9)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物；和(10)着色剂。Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or Any of: (1) bulking or bulking agents such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethyl cellulose, alginate , Gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates And sodium carbonate; (5) solution blockers, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; (8) ) Adsorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) colorants.
液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
除活性成分以外，液体剂型可含有本领域常用惰性稀释剂(诸如，例如，水或其它溶剂)、增溶剂和乳化剂(诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、油类(具体来说，棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇和脱水山梨醇的脂肪酸酯、以及其混合物。In addition to the active ingredient, liquid dosage forms may contain inert diluents (such as, for example, water or other solvents), solubilizers, and emulsifiers (such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol Fatty acid esters of alcohols and sorbitan, and mixtures thereof.
除活性化合物以外，悬浮液可含有悬浮剂，如例如乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶、以及其混合物。In addition to the active compound, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth , And mixtures thereof.
除活性化合物以外，软膏剂、糊剂、乳霜和凝胶可含有赋形剂，诸如动物和植物脂肪、油类、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌、或其混合物。In addition to active compounds, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols , Silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.
除活性化合物以外，散剂和喷雾剂可含有赋形剂，诸如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末、或这些物质的混合物。In addition to the active compounds, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or a mixture of these materials.
喷雾剂另外可含有常规推进剂(诸如氯氟烃)和挥发性未经取代的烃(诸如丁烷和丙烷)。Sprays may additionally contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons (such as butane and propane).
所述制剂可方便地以单位剂型呈递且可通过药剂学领域熟知的任何方法来制备。The formulations are conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical arts.
可与载体材料组合以产生单一剂型的活性成分的量将依据待治疗宿主、具体施用模式而变。The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host to be treated, the particular mode of administration.
可与载体材料组合以产生单一剂型的活性成分的量将通常为所述化合物产生疗效的量。The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount that the compound produces a therapeutic effect.
用于局部或经皮施用的本发明化合物的剂型包括散剂、喷雾剂、软膏剂、糊剂、乳霜、洗剂、凝胶剂、溶液剂、贴剂和吸入剂。Dosage forms of the compounds of this invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
所述活性化合物可在无菌条件下与药学上可接受的载体并且与可能需要的任何防腐剂、缓冲剂或推进剂混合。The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.
当本文所公开化合物作为药物施用给人类和动物时，其可本身或作为含有(例如)0.1％至99.5％(更优选地，0.5％至90％)的活性成分与药学上可接受的载体的组合的药物组合物给予。When a compound disclosed herein is administered to humans and animals as a medicament, it can be used by itself or as an active ingredient containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) and a pharmaceutically acceptable carrier. The combined pharmaceutical composition is administered.
所述制剂可局部、经口、经皮、直肠、阴道、肠胃外(parentally)、鼻内、肺内、眼内、静脉内、肌内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、表皮下或通过吸入而施用。The formulation can be topical, oral, transdermal, rectal, vaginal, parentally, intranasal, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, peritoneal Administration is intradermal, subcutaneous, subcutaneous, or by inhalation.
适应症Indication
FGFR-4在肝细胞癌(HCC)进展期间调控增殖、存活和α-胎蛋白分泌；FGFR-4抑制剂因此是用于此未满足医疗需要的有希望的潜在治疗剂(Ho等人，Journal of Hepatology,2009,50:118-27)。FGFR-4 regulates proliferation, survival, and alpha-fetoprotein secretion during the progression of hepatocellular carcinoma (HCC); FGFR-4 inhibitors are therefore promising potential therapeutic agents for this unmet medical need (Ho et al., Journal of Hepatology, 2009, 50: 118-27).
HCC每年折磨全世界超过550,000人且是任何癌症类型中1年存活率最差者之一。经由FGF19(纤维母细胞生长因子(FGF)家族成员， 其由激素组成)参与调控血糖、血脂和能量稳态显示了FGFR-4与HCC间的联系的其它证据。已在FGF19基因转殖小鼠中观察到增加的肝细胞增殖和肝肿瘤形成。FGF19活化FGFR-4(其在肝中的主要受体)，且认为FGFR-4活化是FGF19能够增加肝细胞增殖并诱导肝细胞癌形成的机制(Wu等人，J Biol Chem(2010)285(8):5165-5170)。FGF19还已被他人识别为HCC中的驱动基因(Sawey等人，Cancer Cell(2011)19:347-358)。因此，认为本文所公开化合物(其是FGFR-4的潜在和选择性抑制剂)可用于治疗HCC和其它肝癌。肿瘤基因组筛查已在人类乳腺癌细胞系MDA-MB-453中鉴定出活化纤维母细胞生长因子受体4(FGFR-4)Y367C突变。因此，其已表明FGFR-4可能为乳腺癌中肿瘤生长的驱动物(Roidl等人，Oncogene(2010)29(10):1543-1552)。因此，认为本文所公开化合物(其为FGFR-4的强效选择性抑制剂)可用于治疗FGFR-4调节的乳腺癌。FGFR-4上游基因的分子变化(例如，易位)会导致FGFR-4活化/过表达。例如，PAX3-FKHR易位/基因融合会导致FGFR-4过表达。因此机制所致的FGFR-4过表达与横纹肌肉瘤(RMS)相关联(Cao等人，Cancer Res(2010)70(16):6497-6508)。FGFR-4自身中的突变(例如，激酶结构域突变)会导致蛋白质过活化；此机制已与RMS亚族群相关(Taylor等人，J Clin Invest(2009)119:3395-3407)。因此，认为本文所公开化合物(其为FGFR-4的强效选择性抑制剂)可用于治疗FGFR-4调节的RMS和其它肉瘤。其它疾病与FGFR-4上游基因的变化或与FGFR-4自身中的突变相关联。例如，FGFR-4的激酶结构域中的突变导致过活化，其与肺腺癌相关(Ding等人，Nature(2008)455(7216):1069-1075)。FGFR-4的扩增与诸如肾细胞癌的病状相关(TCGA暂行资料)。另外，使FGFR4沉默且抑制配体-受体结合显著减慢卵巢肿瘤生长，从而表明FGFR4的抑制剂可用于治疗卵巢癌。(Zaid等人,Clin.Cancer Res.(2013)809)。胆汁酸水平的致病性升高与FGF19水平变化相关(Vergnes等人，Cell Metabolism(2013)17,916-28)。因此，FGF19的水平降低在促进胆汁酸的合成中且因此在高脂血症的治疗中可具有益处。HCC afflicts more than 550,000 people worldwide each year and is one of the worst 1-year survival rates of any cancer type. Additional evidence for the link between FGFR-4 and HCC is shown through the involvement of FGF19 (a member of the fibroblast growth factor (FGF) family, which consists of hormones) in regulating blood glucose, blood lipids, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have been observed in FGF19 gene transgenic mice. FGF19 activates FGFR-4 (its main receptor in the liver), and FGFR-4 activation is considered to be a mechanism by which FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation (Wu et al., J. Biol Chem (2010) 285 ( 8): 5165-5170). FGF19 has also been identified as a driver gene in HCC (Sawey et al. Cancer Cell (2011) 19: 347-358). Therefore, the compounds disclosed herein, which are potential and selective inhibitors of FGFR-4, are believed to be useful in the treatment of HCC and other liver cancers. Tumor genome screening has identified an activated fibroblast growth factor receptor 4 (FGFR-4) Y367C mutation in the human breast cancer cell line MDA-MB-453. Therefore, it has been suggested that FGFR-4 may be a driver of tumor growth in breast cancer (Roidl et al., Oncogene (2010) 29 (10): 1543-1552). Therefore, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated breast cancer. Molecular changes (eg, translocations) of genes upstream of FGFR-4 can cause FGFR-4 activation / overexpression. For example, PAX3-FKHR translocation / gene fusion can cause FGFR-4 overexpression. FGFR-4 overexpression due to this mechanism is associated with rhabdomyosarcoma (RMS) (Cao et al. Cancer Res (2010) 70 (16): 6497-6508). Mutations in FGFR-4 itself (for example, kinase domain mutations) can lead to protein overactivation; this mechanism has been associated with the RMS subpopulation (Taylor et al., J. Clin Invest (2009) 119: 3395-3407). Therefore, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated RMS and other sarcomas. Other diseases are associated with changes in genes upstream of FGFR-4 or with mutations in FGFR-4 itself. For example, mutations in the kinase domain of FGFR-4 result in over-activation, which is associated with lung adenocarcinoma (Ding et al., Nature (2008) 455 (7216): 1069-1075). FGFR-4 amplification is associated with conditions such as renal cell carcinoma (TCGA provisional data). In addition, silencing FGFR4 and inhibiting ligand-receptor binding significantly slowed ovarian tumor growth, suggesting that inhibitors of FGFR4 can be used to treat ovarian cancer. (Zaid et al., Clin. Cancer Res. (2013) 809). The pathogenic increase in bile acid levels is associated with changes in FGF19 levels (Vergnes et al., Cell Metabolism (2013) 17,916-28). Therefore, reduced levels of FGF19 may have benefits in promoting the synthesis of bile acids and therefore in the treatment of hyperlipidemia.
剂量水平可改变本发明药物组合物中活性成分的实际剂量水平以获得有效达成具体患者的预期治疗反应、组成和施用模式且对患者无毒的活性成分的量。所选剂量水平将取决于多种因素，包括所用本 文所公开具体化合物或其酯、盐或酰胺的活性、施用途径、施用时间、所用具体化合物的排泄速率、治疗持续时间、与所用具体化合物组合使用的其它药物、化合物和/或物质、待治疗患者的年龄、性别、体重、病状、一般健康状况和既往病史以及医学领域中熟知的类似因素。本领域中的普通医师或兽医可容易地确定并开出所需药物组合物的有效量。例如，医师或兽医可以低于所需剂量的水平开始用于药物组合物中的本发明化合物的给药以达成预期疗效并逐渐增加剂量直至达成期望效果。一般来说，本发明化合物的适宜日剂量将为化合物有效产生疗效的最低剂量的量。此有效剂量将通常取决于上文所述因素。通常，用于患者的本发明化合物的剂量将在每天每千克体重约0.0001mg至约100mg。例如，剂量可每天介于10mg与2000mg之间。或者，剂量可介于每天100mg与1000mg之间，或介于每天200mg与600mg之间。如果需要，活性化合物的有效日剂量可按一个、两个、三个、四个或四个以上单独施用的亚剂量在全天中以适当间隔施用，任选以单位剂型施用。The dosage level may alter the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, composition, and mode of administration of a particular patient and is non-toxic to the patient. The selected dosage level will depend on a number of factors, including the activity of the specific compound or its ester, salt or amide used herein, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, and the combination with the specific compound used Other drugs, compounds and / or substances used, age, sex, weight, condition, general health and previous medical history of patients to be treated, and similar factors well known in the medical field. A physician or veterinarian in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin the administration of a compound of the invention for use in a pharmaceutical composition at a level below the required dose to achieve the desired effect and gradually increase the dose until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. This effective dose will usually depend on the factors described above. Generally, the dosage of a compound of the invention for use in a patient will be from about 0.0001 mg to about 100 mg per kilogram of body weight per day. For example, the dose may be between 10 mg and 2000 mg per day. Alternatively, the dose may be between 100 mg and 1000 mg per day, or between 200 mg and 600 mg per day. If desired, the effective daily dose of the active compound may be administered as one, two, three, four or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.
组合和靶向疗法本文所公开的FGFR-4抑制剂可与其它癌症治疗组合施用。例如，所述抑制剂可与手术治疗、放射或其它治疗剂(诸如抗体)、其它选择性激酶抑制剂或化学治疗剂组合施用。所述抑制剂还可与RNAi疗法或反义疗法组合施用。本文所述FGFR-4抑制剂可与一种、两种或两种以上其它治疗剂组合。在下文所概述的实施例中，应理解，“第二治疗剂”还包括一种以上除FGFR-4抑制剂以外的治疗剂。例如，本文所公开化合物可与诸如索拉非尼等药剂组合。本文所述FGFR-4抑制剂可与一种、两种或两种以上其它治疗剂一起施用。本文所述FGFR-4抑制剂和第二治疗剂不必于同一药物组合物中施用，且由于不同的物理和化学特性可通过不同途径施用。例如，FGFR-4抑制剂可经口施用，而第二治疗剂为静脉内施用。施用模式和施用合理性的确定(如果可能，以同一药物组合物)完全在熟练临床医师的知识范围内。可根据本领域已知所建立方案进行初始施用，且然后熟练临床医师可基于所观察到的效果改变剂量、施用模式和施用时间。FGFR-4抑制剂和第二治疗剂可同时施用(例如，同时，基本上同时或在同一治疗方案内)或相继(即，一个接着另一个，以其间的任 意时间间隔)，此取决于增殖性疾病的性质、患者病状和实际选择的待施用的第二治疗剂。Combination and targeted therapies The FGFR-4 inhibitors disclosed herein can be administered in combination with other cancer treatments. For example, the inhibitor may be administered in combination with surgical treatment, radiation or other therapeutic agents (such as antibodies), other selective kinase inhibitors, or chemotherapeutic agents. The inhibitor may also be administered in combination with RNAi therapy or antisense therapy. The FGFR-4 inhibitors described herein can be combined with one, two, or more other therapeutic agents. In the examples outlined below, it is understood that the "second therapeutic agent" also includes more than one therapeutic agent other than the FGFR-4 inhibitor. For example, the compounds disclosed herein can be combined with agents such as sorafenib. The FGFR-4 inhibitors described herein can be administered with one, two, or more other therapeutic agents. The FGFR-4 inhibitor and the second therapeutic agent described herein need not be administered in the same pharmaceutical composition, and may be administered by different routes due to different physical and chemical properties. For example, the FGFR-4 inhibitor can be administered orally, while the second therapeutic agent is administered intravenously. The determination of the mode of administration and the rationality of administration (if possible, with the same pharmaceutical composition) is entirely within the knowledge of the skilled clinician. Initial administration can be performed according to established protocols known in the art, and then the skilled clinician can change the dosage, mode of administration, and time of administration based on the observed effects. The FGFR-4 inhibitor and the second therapeutic agent may be administered simultaneously (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially (i.e., one after the other, at any time interval therebetween), depending on proliferation The nature of the sexual disease, the condition of the patient, and the second therapeutic agent to be administered actually selected.
另外，本文所公开FGFR-4抑制剂可作为抗体-药物缀合物的一部分施用，其中FGFR-4抑制剂是缀合物的“有效载荷”部分。Additionally, the FGFR-4 inhibitors disclosed herein can be administered as part of an antibody-drug conjugate, where the FGFR-4 inhibitor is the "payload" portion of the conjugate.
合成本发明化合物(包括其盐和N-氧化物)可使用已知有机合成技术来制备，且可按照多种可能合成途径中的任一种(诸如下文方案中的那些)来合成。用于制备本发明化合物的反应可在合适的溶剂中进行，有机合成领域的技术人员可容易地选择溶剂。合适的溶剂可在进行反应的温度(例如，在溶剂结冻温度至溶剂沸点温度范围内的温度)下与起始物质(反应物)、中间体或产物实质上不反应。既定反应可在一种溶剂或一种以上溶剂的混合物中进行。技术人员可依据具体反应步骤来选择适用于具体反应步骤的溶剂。本发明化合物的制备可涉及不同化学基团的保护和去除保护。本领域技术人员可容易地判定是否需要保护和去除保护以及适当保护基的选择。保护基的化学性质可参见例如Wuts和Greene,Protective Groups in Organic Synthesis,第4版,John Wiley&Sons:New Jersey,(2006),其通过引用整体并入本文中。可按照本领域已知任何合适的方法来监测反应。例如，可通过光谱手段(诸如核磁共振(NMR)光谱法(例如 1H或 13C)、红外(IR)光谱法、分光光度法(例如，UV-可见光)、质谱(MS))或通过色谱方法(诸如高效液相色谱法(HPLC)或薄层色谱法(TLC))来监测产物形成。 Synthesis The compounds of the invention, including their salts and N-oxides, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic pathways, such as those in the schemes below. The reaction for preparing the compound of the present invention can be performed in a suitable solvent, and those skilled in the art of organic synthesis can easily select a solvent. Suitable solvents may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is performed (eg, a temperature in the range of the solvent freezing temperature to the solvent boiling temperature). A given reaction may be performed in one solvent or a mixture of more than one solvent. The skilled person can select a solvent suitable for a specific reaction step depending on the specific reaction step. The preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the selection of an appropriate protecting group. The chemical nature of the protecting group can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety. The reaction can be monitored according to any suitable method known in the art. For example, spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry (MS)), or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.
以下实例意欲为说明性的，且并非意谓以任何方式进行限制。下文方案意欲结合制备本发明化合物来提供一般指导。本领域技术人员应理解，可使用有机化学的一般常识对方案中所示制备加以修改或优化来制备本发明各化合物。The following examples are intended to be illustrative and are not meant to be limiting in any way. The following schemes are intended to provide general guidance in conjunction with the preparation of compounds of the invention. Those skilled in the art will understand that the general knowledge of organic chemistry can be used to modify or optimize the preparations shown in the schemes to prepare the compounds of the invention.
合成实施例Synthesis Example
如未特别说明，本文所用试剂均为市售商品，未经纯化。溶剂使用前均重蒸。监测反应用薄层硅胶板(TLC，GF254,60-F250,0.2mm，烟台江友硅胶薄层色谱)。快速柱层析用谱科化工硅胶(ZCX-II，200-300目)。NMR采用Bruker Advance 400(1H：400MHz；13C：100MHz)或Bruker Advance 500(1H：500MHz；13C：125MHz)核磁共振仪测定，并以TMS为内标。高分辨质谱(HRMS)采用ABI Q-star Elite高分辨质谱仪；终产物纯度检测采用高效液相(HPLC) Agilent 1260系列色谱仪(Agilent PN959990-902Eclipse Plus C18(250mm×4.6mm)色谱柱)检测波长为254纳米。Unless otherwise specified, the reagents used herein are all commercially available products without purification. The solvents were re-distilled before use. The reaction was monitored by a thin layer silica gel plate (TLC, GF254, 60-F250, 0.2mm, Yantai Jiangyou Silica Gel Thin Layer Chromatography). Spectra Chemical Silica Gel (ZCX-II, 200-300 mesh) for flash column chromatography. NMR was measured using Bruker Advance 400 (1H: 400MHz; 13C: 100MHz) or Bruker Advance 500 (1H: 500MHz; 13C: 125MHz) nuclear magnetic resonance instrument, with TMS as the internal standard. High-resolution mass spectrometry (HRMS) using ABI Q-star Elite high-resolution mass spectrometer; final product purity detection using high-performance liquid phase (HPLC) Agilent 1260 series chromatography (Agilent PN959990-902Eclipse Plus C18 (250mm × 4.6mm) column) The wavelength is 254 nm.
以下实施例中使用的缩写按有机合成领域中的常规含义解释，例如下列缩写具有如下含义。The abbreviations used in the following examples are interpreted according to the conventional meanings in the field of organic synthesis. For example, the following abbreviations have the following meanings.
ArCHOArCHO 芳基醛(任选被取代的)Aryl aldehyde (optionally substituted)
BocBoc 叔丁氧基羰基Tert-butoxycarbonyl
DCMDCM 二氯甲烷Dichloromethane
DDQDDQ 2,3-二氯-5,6-二氰基-1,4-苯醌2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DIEADIEA N,N-二异丙基乙胺N, N-diisopropylethylamine
DMAPDMAP 4-二甲氨基吡啶4-dimethylaminopyridine
DMFDMF 二甲基甲酰胺dimethylformamide
DMSODMSO 二甲基亚砜Dimethyl sulfoxide
EAEA 乙酸乙酯Ethyl acetate
Et 3N Et 3 N 三乙基胺Triethylamine
Et 3SiH Et 3 SiH 三乙基硅烷Triethylsilane
EtOAcEtOAc 乙酸乙酯Ethyl acetate
m-CPBAm-CPBA 间-氯过氧苯甲酸M-chloroperoxybenzoic acid
MeOHMeOH 甲醇Methanol
NISNIS N-碘代丁二酰亚胺N-iodosuccinimide
Pd(dppf)Cl 2 Pd (dppf) Cl 2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯[1,1'-Bis (diphenylphosphino) ferrocene] Palladium dichloride
AcAc 乙酰基Acetyl
PhPh 苯基Phenyl
Pd 2(dba) 3 Pd 2 (dba) 3 三(二亚苄基丙酮)二钯(0)Tris (dibenzylideneacetone) dipalladium (0)
SEM-ClSEM-Cl 2-(三甲硅烷基)乙氧甲基氯2- (trimethylsilyl) ethoxymethyl chloride
TFATFA 三氟乙酸Trifluoroacetate
THFTHF 四氢呋喃Tetrahydrofuran
X-phosX-phos 2-二环己基磷-2′,4′,6′-三异丙基联苯2-dicyclohexyl phosphorus-2 ′, 4 ′, 6′-triisopropylbiphenyl
Xant-phosXant-phos 4,5-双二苯基膦-9,9-二甲基氧杂蒽4,5-bisdiphenylphosphine-9,9-dimethylxanthene
Figure PCTCN2019090131-appb-000021
Figure PCTCN2019090131-appb-000021
条件和试剂：Conditions and reagents:
(a)2-硝基苯胺,Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜； (a) 2-nitroaniline, Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 degrees Celsius, overnight;
(b)NIS,DMF,室温；(b) NIS, DMF, room temperature;
(c)(3,5-二甲氧基苯基)硼酸,Pd(dppf)Cl 2,1,4-二氧六环:H2O＝3:1,100摄氏度,微波1h, (c) (3,5-dimethoxyphenyl) boronic acid, Pd (dppf) Cl 2 , 1,4-dioxane: H2O = 3: 1,100 degrees Celsius, microwave for 1 h,
(d)H 2,Pd/C,EtOAc,室温； (d) H 2 , Pd / C, EtOAc, room temperature;
(e)丙烯酰氯,DIEA,THF,0摄氏度,然后室温(e) Acryloyl chloride, DIEA, THF, 0 ° C, and then room temperature
Figure PCTCN2019090131-appb-000022
Figure PCTCN2019090131-appb-000022
条件和试剂：Conditions and reagents:
Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜 Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 ° C, overnight
N-(2-硝基苯基)-1H-吡咯并[2,3-b]吡啶-6-胺(I1)：将6-氯-7-氮杂吲哚(0.50g，3.3mmol)、2-硝基苯胺(0.50g，3.6mmol)、Pd 2(dba) 3(0.30g，0.33mmol)、X-Phos(0.31g，0.66mmol)、碳酸钾(0.91g，6.6mmol)溶于无水1,4-二氧六环(25mL)，通入氩气除氧。反应液在110℃条件下搅拌过夜，冷却至室温，过滤，加入水和乙酸乙酯(3×60mL)萃取，收集有机相，饱和食盐水(2×30mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.49g，产率58％。 1H NMR(400 MHz,氯仿-d)δ10.24(s,1H),9.03(s,1H),8.61(dd,J＝8.8,1.3Hz,1H),8.25(dd,J＝8.5,1.7Hz,1H),7.91(d,J＝8.3Hz,1H),7.52(ddd,J＝8.7,7.0,1.6Hz,1H),7.11(dd,J＝3.6,2.4Hz,1H),6.91(ddd,J＝8.4,7.0,1.3Hz,1H),6.85(d,J＝8.3Hz,1H),6.47(dd,J＝3.6,2.1Hz,1H). 13C NMR(101MHz,CDCl 3)δ148.33,146.67,140.00,135.76,131.27,126.44,123.25,119.00,118.90,115.88,108.62,101.61. N- (2-nitrophenyl) -1H-pyrrolo [2,3-b] pyridine-6-amine (I1): 6-chloro-7-azaindole (0.50 g, 3.3 mmol), 2-nitroaniline (0.50g, 3.6mmol), Pd 2 (dba) 3 (0.30g, 0.33mmol), X-Phos (0.31g, 0.66mmol), potassium carbonate (0.91g, 6.6mmol) dissolved in Water 1,4-dioxane (25 mL) was purged with argon to remove oxygen. The reaction solution was stirred at 110 ° C overnight, cooled to room temperature, filtered, and extracted by adding water and ethyl acetate (3 × 60 mL). The organic phase was collected, washed with saturated brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated. After purification by column chromatography, 0.49 g of a yellow solid was obtained with a yield of 58%. 1 H NMR (400 MHz, chloroform-d) δ 10.24 (s, 1H), 9.03 (s, 1H), 8.61 (dd, J = 8.8, 1.3 Hz, 1H), 8.25 (dd, J = 8.5, 1.7 Hz, 1H), 7.91 (d, J = 8.3Hz, 1H), 7.52 (ddd, J = 8.7, 7.0, 1.6Hz, 1H), 7.11 (dd, J = 3.6, 2.4Hz, 1H), 6.91 (ddd , J = 8.4,7.0,1.3Hz, 1H), 6.85 (d, J = 8.3Hz, 1H), 6.47 (dd, J = 3.6,2.1Hz, 1H). 13 C NMR (101MHz, CDCl 3) δ148. 33,146.67,140.00,135.76,131.27,126.44,123.25,119.00,118.90,115.88,108.62,101.61.
Figure PCTCN2019090131-appb-000023
Figure PCTCN2019090131-appb-000023
条件和试剂：NIS,DMF,室温Conditions and reagents: NIS, DMF, room temperature
3-碘-N-(2-硝基苯基)-1H-吡咯并[2,3-b]吡啶-6-胺(I2)：将化合物I1(0.39g，1.6mmol)溶于无水DMF(4.0mL)，0℃搅拌下加入NIS(0.38g，1.7mmol)。反应液在室温下搅拌2h后，加水稀释，乙酸乙酯(3×80mL)萃取，收集有机相和食盐水(2×40mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.37g，产率61％。 1H NMR(400MHz,DMSO-d 6)δ11.80(s,1H),9.81(s,1H),8.32(d,J＝8.4Hz,1H),8.07(dd,J＝8.5,1.6Hz,1H),7.67-7.63(m,1H),7.59(d,J＝8.4Hz,1H),7.42(d,J＝2.5Hz,1H),7.06(t,J＝7.5Hz,1H),6.91(d,J＝8.4Hz,1H). 13C NMR(101MHz,DMSO)δ150.34,146.22,137.82,137.34,135.52,130.95,128.30,126.21,121.71,120.91,117.51,108.35,55.14. 3-iodo-N- (2-nitrophenyl) -1H-pyrrolo [2,3-b] pyridine-6-amine (I2): Compound I1 (0.39 g, 1.6 mmol) was dissolved in anhydrous DMF (4.0 mL), and NIS (0.38 g, 1.7 mmol) was added with stirring at 0 ° C. The reaction solution was stirred at room temperature for 2h, diluted with water, extracted with ethyl acetate (3 × 80mL), collected the organic phase and brine (2 × 40mL), washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.37 as a yellow solid. g, yield 61%. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.80 (s, 1H), 9.81 (s, 1H), 8.32 (d, J = 8.4Hz, 1H), 8.07 (dd, J = 8.5, 1.6Hz, 1H), 7.67-7.63 (m, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.42 (d, J = 2.5Hz, 1H), 7.06 (t, J = 7.5Hz, 1H), 6.91 ( d, J = 8.4Hz, 1H). 13 C NMR (101MHz, DMSO) δ 150.34, 146.22, 137.82, 137.34, 135.52, 130.95, 128.30, 126.21, 121.71, 120.91, 117.51, 108.35, 55.14.
Figure PCTCN2019090131-appb-000024
Figure PCTCN2019090131-appb-000024
条件和试剂：Pd(dppf)Cl 2,1,4-二氧六环:H2O＝3:1,100摄氏度,微波,1h Conditions and reagents: Pd (dppf) Cl 2 , 1,4-dioxane: H2O = 3: 1,100 ° C, microwave, 1h
3-(3,5-二甲氧基苯基)-N-(2-硝基苯基)-1H-吡咯并[2,3-b]吡啶-6- 胺(I3)：将化合物I2(0.15g，0.39mmol)、3,5-二甲氧基苯硼酸(0.11g，0.59mmol)、Pd(dppf)Cl 2(0.39g，1.6mmol)、碳酸钾(0.16g，1.2mmol)溶于1,4-二氧六环和水(3：1)的混合溶剂(4mL)，通入氩气除氧。反应液在微波反应器中、100℃条件下反应1h，冷却至室温，过滤，往滤液中加入水和乙酸乙酯(3×40mL)萃取，收集有机相，饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体61m g，产率40％。 1H NMR(400MHz,DMSO-d 6)δ11.67(s,1H),9.84(s,1H),8.40(d,J＝8.6Hz,1H),8.19(d,J＝8.5Hz,1H),8.09(d,J＝8.4Hz,1H),7.64(d,J＝10.6Hz,2H),7.05(t,J＝7.8Hz,1H),6.94(d,J＝8.4Hz,1H),6.89-6.64(m,2H),6.50-6.26(m,1H),3.79(s,6H). 13C NMR(101MHz,DMSO)δ161.34,149.29,147.33,138.27,137.60,136.79,135.63,130.62,126.27,122.24,121.32,120.52,115.43，113.00，107.97，104.67，98.32，55.69. 3- (3,5-dimethoxyphenyl) -N- (2-nitrophenyl) -1H-pyrrolo [2,3-b] pyridine-6-amine (I3): Compound I2 ( 0.15g, 0.39mmol), 3,5- dimethoxybenzene boronic acid (0.11g, 0.59mmol), Pd ( dppf) Cl 2 (0.39g, 1.6mmol), potassium carbonate (0.16g, 1.2mmol) was dissolved in A mixed solvent (4 mL) of 1,4-dioxane and water (3: 1) was purged with argon to remove oxygen. The reaction solution was reacted in a microwave reactor at 100 ° C for 1 hour, cooled to room temperature, and filtered. Water and ethyl acetate (3 × 40 mL) were added to the filtrate for extraction. The organic phase was collected and washed with saturated brine (2 × 20 mL). , dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow solid 61m g, yield 40%. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.67 (s, 1H), 9.84 (s, 1H), 8.40 (d, J = 8.6Hz, 1H), 8.19 (d, J = 8.5Hz, 1H) , 8.09 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 10.6 Hz, 2H), 7.05 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.89 -6.64 (m, 2H), 6.50-6.26 (m, 1H), 3.79 (s, 6H). 13 C NMR (101MHz, DMSO) δ161.34,149.29,147.33,138.27,137.60,136.79,135.63,130.62,126.27, 122.24, 121.32, 120.52, 115.43, 113.00, 107.97, 104.67, 98.32, 55.69.
Figure PCTCN2019090131-appb-000025
Figure PCTCN2019090131-appb-000025
条件和试剂：H 2,Pd/C,EtOAc,室温； Conditions and reagents: H 2 , Pd / C, EtOAc, room temperature;
N1-(3-(3,5-二甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)苯-1,2-二胺(I4)：将化合物I3(61mg，0.16mmol)溶于乙酸乙酯，加入10％Pd/C，氢气(1atm)还原室温搅拌过夜，过滤，收集滤液，浓缩得到白色固体中间体I4(36mg)，不需经过纯化可直接用于下一步反应。N1- (3- (3,5-dimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) benzene-1,2-diamine (I4): Compound I3 (61mg, 0.16mmol) was dissolved in ethyl acetate, 10% Pd / C was added, and reduced by hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate was collected, and concentrated to give a white solid intermediate I4 (36mg), which can be directly used without purification. Used for the next reaction.
Figure PCTCN2019090131-appb-000026
Figure PCTCN2019090131-appb-000026
条件和试剂：DIEA,THF,0摄氏度,然后室温Conditions and reagents: DIEA, THF, 0 ° C, then room temperature
N-(2-((3-(3,5-二甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(1)：将化合物I4(36mg，0.10mmol)溶于四氢呋喃(2.0mL)，冰水浴条件下，依次加入DIEA(33μL，0.20mmol)和丙烯酰氯(9.7μL，0.12mmol)，室温反应30min。浓缩后加入水(10mL)和乙酸乙酯(3×10mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体25mg，产率61％。 1H NMR(400MHz,DMSO-d 6)δ11.46(d,J＝2.6Hz,1H),9.81(s,1H),8.12(s,1H),8.06(d,J＝8.6Hz,1H),7.88-7.77(m,1H),7.63-7.55(m,1H),7.50(d,J＝2.5Hz,1H),7.15(td,J＝7.7,1.6Hz,1H),7.02(td,J＝7.7,1.5Hz,1H),6.76(d,J＝2.3Hz,2H),6.69(d,J＝8.6Hz,1H),6.47(dd,J＝17.0,10.1Hz,1H),6.35(t,J＝2.2Hz,1H),6.23(dd,J＝17.0,2.0Hz,1H),5.72(dd,J＝10.1,2.0Hz,1H),3.78(s,6H). 13C NMR(101MHz,DMSO)δ164.14,161.30,152.47,147.99,137.98,135.08,132.51,130.31,129.72,127.14,125.81,125.39,122.74,122.65,120.46,115.38,110.92,105.41,104.55,98.08,55.66.HRMS(ESI)m/z C 24H 22N 4O 3[M+H] +的计算值414.1692；实测值415.1767. N- (2-((3- (3,5-dimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (1): Compound I4 (36 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2.0 mL), and DIEA (33 μL, 0.20 mmol) and acryloyl chloride (9.7 μL, 0.12 mmol) were sequentially added under ice-water bath conditions, and the reaction was performed at room temperature for 30 min. After concentration, water (10 mL) and ethyl acetate (3 × 10 mL) were added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 25 mg of a white solid with a yield of 61%. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.46 (d, J = 2.6 Hz, 1H), 9.81 (s, 1H), 8.12 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H) , 7.88-7.77 (m, 1H), 7.63-7.55 (m, 1H), 7.50 (d, J = 2.5Hz, 1H), 7.15 (td, J = 7.7, 1.6Hz, 1H), 7.02 (td, J = 7.7, 1.5Hz, 1H), 6.76 (d, J = 2.3Hz, 2H), 6.69 (d, J = 8.6Hz, 1H), 6.47 (dd, J = 17.0, 10.1Hz, 1H), 6.35 (t , J = 2.2Hz, 1H), 6.23 (dd, J = 17.0,2.0Hz, 1H), 5.72 (dd, J = 10.1,2.0Hz, 1H), 3.78 (s, 6H). 13 C NMR (101MHz, DMSO) δ164.14,161.30,152.47,147.99,137.98,135.08,132.51,130.31,129.72,127.14,125.81,125.39,122.74,122.65,120.46,115.38,110.92,105.41,104.55,98.08,55.66.HRMS (ESI) m Calculated value of z C 24 H 22 N 4 O 3 [M + H] + 414.1692; found 415.1767.
Figure PCTCN2019090131-appb-000027
Figure PCTCN2019090131-appb-000027
条件和试剂：Conditions and reagents:
(a)3-甲氧基苯甲醛,NaOH,DMSO,空气,100摄氏度；(a) 3-methoxybenzaldehyde, NaOH, DMSO, air, 100 degrees Celsius;
(b)SEM-Cl,NaH,DMF,0摄氏度,然后室温；(b) SEM-Cl, NaH, DMF, 0 degrees Celsius, and then room temperature;
(c)2-硝基苯胺,Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜； (c) 2-nitroaniline, Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 degrees Celsius, overnight;
(d)i)TFA/DCM,ii)K 2CO 3,MeOH,室温； (d) i) TFA / DCM, ii) K 2 CO 3 , MeOH, room temperature;
(e)m-CPBA,DCM,室温；(e) m-CPBA, DCM, room temperature;
(f)H 2,Pd/C,EtOAc,室温； (f) H 2 , Pd / C, EtOAc, room temperature;
(g)丙烯酰氯,DIEA,THF,0摄氏度,然后室温(g) Acryloyl chloride, DIEA, THF, 0 degrees Celsius, and then room temperature
Figure PCTCN2019090131-appb-000028
Figure PCTCN2019090131-appb-000028
条件和试剂：NaOH,DMSO,空气,100摄氏度Conditions and reagents: NaOH, DMSO, air, 100 degrees Celsius
6-氯-3-((3-甲氧基苯基)硫代)-1H-吡咯并[2,3-b]吡啶(I5)：将6-氯-7-氮杂吲哚(0.3g，2.0mmol)溶于DMSO(5.0mL)，依次加入氢氧化钠(0.16g，3.9mmol)、3-甲氧基苯硫酚(0.55g，0.49mL，3.9mmol)。反应液加热至100℃、在空气氛围下搅拌反应过夜，TLC监测反应结束后，加水(50mL)稀释，乙酸乙酯(3×50mL)萃取，收集有机相，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体0.52g，产率89％。 1H NMR(400MHz,DMSO)δ12.51(s,1H),7.98(d,J＝2.5Hz,1H),7.82(d,J＝8.2Hz,1H),7.22-7.16(m,1H),7.16-7.10(m,1H),6.68(ddd,J＝8.2,2.3,1.0Hz,1H),6.58(ddd,J＝2.5,1.9,1.0Hz,2H),3.64(s,3H). 13C NMR(101MHz,DMSO)δ160.18,148.21,144.68,140.11,134.40,130.53,130.47,120.53,118.37,117.07,111.84,111.24,99.91,55.54. 6-chloro-3-((3-methoxyphenyl) thio) -1H-pyrrolo [2,3-b] pyridine (I5): 6-chloro-7-azaindole (0.3 g , 2.0 mmol) was dissolved in DMSO (5.0 mL), and sodium hydroxide (0.16 g, 3.9 mmol) and 3-methoxythiophenol (0.55 g, 0.49 mL, 3.9 mmol) were added in this order. The reaction solution was heated to 100 ° C, and the reaction was stirred under air atmosphere overnight. After the reaction was monitored by TLC, it was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and column Purification by chromatography gave 0.52 g of a white solid with a yield of 89%. 1 H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.22-7.16 (m, 1H), 7.16-7.10 (m, 1H), 6.68 (ddd, J = 8.2, 2.3, 1.0Hz, 1H), 6.58 (ddd, J = 2.5, 1.9, 1.0Hz, 2H), 3.64 (s, 3H). 13 C NMR (101MHz, DMSO) δ 160.18, 148.21, 144.68, 140.11, 134.40, 130.53, 130.47, 120.53, 118.37, 117.07, 111.84, 111.24, 99.91, 55.54.
Figure PCTCN2019090131-appb-000029
Figure PCTCN2019090131-appb-000029
条件和试剂：SEM-Cl,NaH,DMF,0摄氏度,然后室温Conditions and reagents: SEM-Cl, NaH, DMF, 0 ° C, then room temperature
6-氯-3-((3-甲氧基苯基)硫代)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(I6)：将化合物I5(0.10g，0.35mmol)溶于无水DMF(2.0mL)，0℃搅拌下加入60％氢化钠(0.021g，0.53mmol)。反应液在0℃下搅拌30min后，加入SEM-Cl(0.087g，0.093mL，0.53mmol)，升至室温搅拌2h。TLC监测反应完全，加水(10mL)稀释，乙酸乙酯(3×10mL)萃取，收集有机相，无水硫酸钠干 燥，浓缩，柱层析纯化得到无色油状液体0.14g，产率95％。 1H NMR(500MHz,CDCl 3)δ7.79(d,J＝8.2Hz,1H),7.61(s,1H),7.13(d,J＝8.2Hz,1H),7.10(dd,J＝8.8,7.8Hz,1H),6.68-6.62(m,3H),5.67(s,2H),3.70(s,3H),3.62-3.57(m,2H),0.97-0.91(m,2H),-0.05(s,9H). 13C NMR(101MHz,CDCl 3)δ160.06,147.64,146.11,139.44,134.03,130.61,129.81,120.59,118.65,117.71,112.13,110.88,102.66,73.13,66.85,55.24,17.82,-1.37. 6-chloro-3-((3-methoxyphenyl) thio) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3 -b] pyridine (I6): Compound I5 (0.10 g, 0.35 mmol) was dissolved in anhydrous DMF (2.0 mL), and 60% sodium hydride (0.021 g, 0.53 mmol) was added under stirring at 0 ° C. After the reaction solution was stirred at 0 ° C for 30 min, SEM-Cl (0.087 g, 0.093 mL, 0.53 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC for complete reaction, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.14 g of a colorless oily liquid with a yield of 95%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.79 (d, J = 8.2 Hz, 1 H), 7.61 (s, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.10 (dd, J = 8.8, 7.8Hz, 1H), 6.68-6.62 (m, 3H), 5.67 (s, 2H), 3.70 (s, 3H), 3.62-3.57 (m, 2H), 0.97-0.91 (m, 2H), -0.05 ( s, 9H). 13 C NMR (101MHz, CDCl 3) δ160.06,147.64,146.11,139.44,134.03,130.61,129.81,120.59,118.65,117.71,112.13,110.88,102.66,73.13,66.85,55.24,17.82, -1.37 .
Figure PCTCN2019090131-appb-000030
Figure PCTCN2019090131-appb-000030
条件和试剂：Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜 Conditions and reagents: Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 ° C, overnight
3-((3-甲氧基苯基)硫代)-N-(2-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-6-胺(I7)：将化合物I6(0.14g，0.33mmol)、2-甲基-6-硝基苯胺(0.051g，0.37mmol)、Pd 2(dba) 3(0.030g，0.033mmol)、X-Phos(0.032g，0.067mmol)、碳酸钾(0.0.093g，0.67mmol)溶于无水1,4-二氧六环(4.0mL)，通入氩气除氧。反应液在110℃条件下搅拌过夜，冷却至室温，过滤，往滤液中加入水(20mL)和乙酸乙酯(3×20mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.15g，产率87％。 3-((3-methoxyphenyl) thio) -N- (2-nitrophenyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H -Pyrrolo [2,3-b] pyridine-6-amine (I7): Compound I6 (0.14 g, 0.33 mmol), 2-methyl-6-nitroaniline (0.051 g, 0.37 mmol), Pd 2 (dba) 3 (0.030 g, 0.033 mmol), X-Phos (0.032 g, 0.067 mmol), potassium carbonate (0.0.093 g, 0.67 mmol) dissolved in anhydrous 1,4-dioxane (4.0 mL), Pass argon to remove oxygen. The reaction solution was stirred at 110 ° C overnight, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 x 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration and purification by column chromatography gave 0.15 g of a yellow solid with a yield of 87%.
1H NMR(400MHz,CDCl3)δ10.39(s,1H),8.96(dd,J＝8.7,1.1Hz,1H),8.26(dd,J＝8.6,1.6Hz,1H),7.83-7.77(m,1H),7.58(ddd,J＝8.6,7.1,1.5Hz,1H),7.50(s,1H),7.13-7.07(m,1H),6.96(ddd,J＝8.4,7.1,1.3Hz,1H),6.81(d,J＝8.4Hz,1H),6.72-6.69(m,1H),6.69-6.67(m,1H),6.64(ddd,J＝8.2,2.4,0.7Hz,1H),5.66(s,2H),3.70(s,3H),3.65-3.60(m,2H),0.97-0.92(m,2H),-0.08(s,9H).13C NMR(101MHz,CDCl3)δ160.04,149.67,146.91,139.97,139.34,135.61,134.56,132.15,130.51,129.75,126.44,119.53,119.42,118.55,117.05,111.99,110.72,109.11,102.55,73.24,66.71,55.25,17.82,-1.38. 1 H NMR (400MHz, CDCl3) δ 10.39 (s, 1H), 8.96 (dd, J = 8.7, 1.1 Hz, 1H), 8.26 (dd, J = 8.6, 1.6 Hz, 1H), 7.83-7.77 (m , 1H), 7.58 (ddd, J = 8.6,7.1,1.5Hz, 1H), 7.50 (s, 1H), 7.13-7.07 (m, 1H), 6.96 (ddd, J = 8.4,7.1,1.3Hz, 1H ), 6.81 (d, J = 8.4Hz, 1H), 6.72-6.69 (m, 1H), 6.69-6.67 (m, 1H), 6.64 (ddd, J = 8.2, 2.4, 0.7Hz, 1H), 5.66 ( s, 2H), 3.70 (s, 3H), 3.65-3.60 (m, 2H), 0.97-0.92 (m, 2H), -0.08 (s, 9H). 13C NMR (101MHz, CDCl3) δ 160.04, 149.67, 146.91 , 139.97,139.34,135.61,134.56,132.15,130.51,129.75,126.44,119.53,119.42,118.55,117.05,111.99,110.72,109.11,102.55,73.24,66.71,55.25,17.82, -1.38.
Figure PCTCN2019090131-appb-000031
Figure PCTCN2019090131-appb-000031
条件和试剂：i)TFA/DCM；ii)K 2CO 3,MeOH,室温； Conditions and reagents: i) TFA / DCM; ii) K 2 CO 3 , MeOH, room temperature;
3-((3-甲氧基苯基)硫代)-N-(2-硝基苯基)-1H-吡咯并[2,3-b]吡啶-6-胺(I8)：将化合物I7(0.63g，1.20mmol)溶于二氯甲烷(3.0mL)，加入三氟乙酸(3.0mL)。反应液在室温搅拌5h，浓缩后得到的固体溶于甲醇(3.0mL)后加入碳酸钾调节pH至12，室温搅拌过夜。TLC监测反应结束后，浓缩，加入水(20mL)和乙酸乙酯(3×20mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体100mg，产率21％。 1H NMR(400MHz,DMSO-d 6)δ11.99(d,J＝2.6Hz,1H),9.81(s,1H),8.38(dd,J＝8.6,1.3Hz,1H),8.08(dd,J＝8.4,1.6Hz,1H),7.69(d,J＝8.4Hz,1H),7.66-7.62(m,2H),7.13(t,J＝8.0Hz,1H),7.07(ddd,J＝8.4,7.1,1.3Hz,1H),6.91(d,J＝8.5Hz,1H),6.66(ddd,J＝8.3,2.5,1.0Hz,1H),6.61-6.56(m,1H),3.63(s,3H). 13C NMR(101MHz,DMSO)δ160.16,150.27,147.21,140.78,137.86,137.28,135.54,131.04,130.43,129.68,126.22,121.72,120.90,118.23,116.35,111.71,110.94,108.48,99.51,55.53. 3-((3-methoxyphenyl) thio) -N- (2-nitrophenyl) -1H-pyrrolo [2,3-b] pyridine-6-amine (I8): Compound I7 (0.63 g, 1.20 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (3.0 mL) was added. The reaction solution was stirred at room temperature for 5 h. The solid obtained after concentration was dissolved in methanol (3.0 mL), potassium carbonate was added to adjust the pH to 12, and the mixture was stirred at room temperature overnight. After the reaction was monitored by TLC, the reaction solution was concentrated and extracted by adding water (20 mL) and ethyl acetate (3 × 20 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 100 mg of a yellow solid. Yield 21%. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.99 (d, J = 2.6 Hz, 1H), 9.81 (s, 1H), 8.38 (dd, J = 8.6, 1.3 Hz, 1H), 8.08 (dd, J = 8.4, 1.6Hz, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.66-7.62 (m, 2H), 7.13 (t, J = 8.0Hz, 1H), 7.07 (ddd, J = 8.4 , 7.1, 1.3Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 6.66 (ddd, J = 8.3, 2.5, 1.0Hz, 1H), 6.61-6.56 (m, 1H), 3.63 (s, 3H). 13 C NMR (101MHz, DMSO) δ 160.16, 150.27, 147.21, 140.78, 137.86, 137.28, 135.54, 131.04, 130.43, 129.68, 126.22, 121.72, 120.90, 118.23, 116.35, 111.71, 110.94, 108.48, 99.51, 55.53 .
Figure PCTCN2019090131-appb-000032
Figure PCTCN2019090131-appb-000032
条件和试剂：H 2,Pd/C,EtOAc,室温 Conditions and reagents: H 2 , Pd / C, EtOAc, room temperature
N1-(3-((3-甲氧基苯基)硫代)-1H-吡咯并[2,3-b]吡啶-6-基)苯-1,2-二胺(I9)：将化合物I8(100mg，0.25mmol)溶于乙酸乙酯，加入10％Pd/C，氢气(1atm)还原室温搅拌过夜，过滤，收集滤液，浓缩得到白色固体中间体I9(69mg)，不需经过纯化可直接用于下一步 反应。N1- (3-((3-methoxyphenyl) thio) -1H-pyrrolo [2,3-b] pyridin-6-yl) benzene-1,2-diamine (I9): Compound I8 (100 mg, 0.25 mmol) was dissolved in ethyl acetate, 10% Pd / C was added, and hydrogen (1 atm) was reduced and stirred at room temperature overnight, filtered, the filtrate was collected, and concentrated to give white solid intermediate I9 (69 mg). Used directly in the next reaction.
Figure PCTCN2019090131-appb-000033
Figure PCTCN2019090131-appb-000033
条件和试剂：DIEA,THF,0摄氏度,然后室温Conditions and reagents: DIEA, THF, 0 ° C, then room temperature
N-(2-((3-((3-甲氧基苯基)硫代)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(2)：将化合物I9(69mg，0.19mmol)溶于四氢呋喃(2.0mL)，冰水浴条件下，依次加入DIEA(63μL，0.38mmol)和丙烯酰氯(18μL，0.23mmol)，室温反应30min。浓缩后加入水(10mL)和乙酸乙酯(3×10mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到土黄色固体23mg，产率29％。1H NMR(400MHz,DMSO-d6)δ11.78(d,J＝2.6Hz,1H),9.74(s,1H),8.16(s,1H),7.81(dd,J＝8.1,1.5Hz,1H),7.60(d,J＝7.9Hz,1H),7.55(d,J＝8.5Hz,1H),7.48(d,J＝2.4Hz,1H),7.19-7.07(m,2H),7.03(td,J＝7.6,1.5Hz,1H),6.69-6.61(m,2H),6.60-6.53(m,2H),6.47(dd,J＝17.0,10.2Hz,1H),6.22(dd,J＝17.1,2.0Hz,1H),5.72(dd,J＝10.1,2.0Hz,1H),3.63(s,3H).13C NMR(101MHz,DMSO)δ164.16,160.15,153.34,147.92,141.14,134.70,132.48,130.35,130.04,129.31,129.28,127.13,125.76,125.28,123.25,122.94,118.06,114.26,111.55,110.75,105.99,99.14,55.52.HRMS(ESI)m/z C 23H 20N 4O 2S[M+H] +的计算值416.1307；实测值417.1382. N- (2-((3-((3-methoxyphenyl) thio))-1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (2) : Compound I9 (69 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2.0 mL), and DIEA (63 μL, 0.38 mmol) and acryloyl chloride (18 μL, 0.23 mmol) were sequentially added under ice-water bath conditions, and reacted at room temperature for 30 min. After concentration, water (10 mL) and ethyl acetate (3 × 10 mL) were added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 23 mg of a khaki solid with a yield of 29%. 1H NMR (400MHz, DMSO-d6) δ 11.78 (d, J = 2.6 Hz, 1H), 9.74 (s, 1H), 8.16 (s, 1H), 7.81 (dd, J = 8.1, 1.5 Hz, 1H) , 7.60 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.19-7.07 (m, 2H), 7.03 (td, J = 7.6, 1.5Hz, 1H), 6.69-6.61 (m, 2H), 6.60-6.53 (m, 2H), 6.47 (dd, J = 17.0, 10.2Hz, 1H), 6.22 (dd, J = 17.1, 2.0Hz, 1H), 5.72 (dd, J = 10.1, 2.0Hz, 1H), 3.63 (s, 3H). 13C NMR (101MHz, DMSO) δ164.16, 160.15, 153.34, 147.92, 141.14, 134.70, 132.48, 130.35, 130.04,129.31,129.28,127.13,125.76,125.28,123.25,122.94,118.06,114.26,111.55,110.75,105.99,99.14,55.52.HRMS (ESI) m / z C 23 H 20 N 4 O 2 S [M + H ] + calcd 416.1307; Found 417.1382.
Figure PCTCN2019090131-appb-000034
Figure PCTCN2019090131-appb-000034
条件和试剂：m-CPBA,DCM,室温Conditions and reagents: m-CPBA, DCM, room temperature
3-((3-甲氧基苯基)亚磺酰基)-N-(2-硝基苯基)-1H-吡咯并[2,3-b]吡啶-6-胺(I10)：将化合物I8(0.29g，0.73mmol)溶于二氯甲烷(5.0mL)，加入m-CPBA(0.13g，0.73mmol)。反应液在室温搅拌2h。TLC监测反应完全后加入饱和硫代硫酸钠溶液(10mL)淬灭反应，二氯甲烷(3×30mL)萃取，收集有机相，饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体175mg，产率59％。MS(ESI):409[M+H] +. 3-((3-methoxyphenyl) sulfinyl) -N- (2-nitrophenyl) -1H-pyrrolo [2,3-b] pyridine-6-amine (I10): Compound I8 (0.29 g, 0.73 mmol) was dissolved in dichloromethane (5.0 mL), and m-CPBA (0.13 g, 0.73 mmol) was added. The reaction was stirred at room temperature for 2h. After the reaction was monitored by TLC, the reaction was quenched by adding a saturated sodium thiosulfate solution (10 mL), and extracted with dichloromethane (3 × 30 mL). The organic phase was collected, washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography gave 175 mg of a yellow solid with a yield of 59%. MS (ESI): 409 [M + H] + .
Figure PCTCN2019090131-appb-000035
Figure PCTCN2019090131-appb-000035
条件和试剂：m-CPBA,DCM,室温Conditions and reagents: m-CPBA, DCM, room temperature
3-((3-甲氧基苯基)磺酰基)-N-(2-硝基苯基)-1H-吡咯并[2,3-b]吡啶-6-胺(I11)：将化合物I8(0.11g，0.28mmol)溶于二氯甲烷(3.0mL)，加入m-CPBA(0.12g，0.28mmol)。反应液在室温搅拌2h。TLC监测反应完全后加入饱和硫代硫酸钠溶液(10mL)淬灭反应，二氯甲烷(3×30mL)萃取，收集有机相，饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体67mg，产率57％。 1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),8.18(dd,J＝8.5,1.3Hz,1H),8.09(d,J＝8.6Hz,1H),8.07-8.01(m,2H),7.64(ddd,J＝8.6,7.2,1.6Hz,1H),7.55(dt,J＝7.8,1.3Hz,1H),7.50(d,J＝8.0Hz,1H),7.46(dt,J＝2.6,1.6Hz,1H),7.18(ddd,J＝8.1,2.6,1.1Hz,1H),7.12(ddd,J＝8.4,7.1,1.3Hz,1H),7.01(d,J＝8.6Hz,1H),3.81(s,3H). 13C NMR(101MHz,DMSO)δ160.06,151.34,146.73,145.01,138.54,136.81,135.28,131.28,130.08,129.58,126.09,122.59,121.72,119.14,118.93,114.82,111.78,110.70,109.62,56.19. 3-((3-methoxyphenyl) sulfonyl) -N- (2-nitrophenyl) -1H-pyrrolo [2,3-b] pyridine-6-amine (I11): Compound I8 (0.11 g, 0.28 mmol) was dissolved in dichloromethane (3.0 mL), and m-CPBA (0.12 g, 0.28 mmol) was added. The reaction was stirred at room temperature for 2h. After the reaction was monitored by TLC, the reaction was quenched by adding a saturated sodium thiosulfate solution (10 mL), and extracted with dichloromethane (3 × 30 mL). The organic phase was collected, washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography gave 67 mg of a yellow solid with a yield of 57%. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 8.18 (dd, J = 8.5, 1.3 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.07-8.01 ( m, 2H), 7.64 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.55 (dt, J = 7.8, 1.3 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (dt , J = 2.6, 1.6Hz, 1H), 7.18 (ddd, J = 8.1, 2.6, 1.1Hz, 1H), 7.12 (ddd, J = 8.4, 7.1, 1.3Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101MHz, DMSO) δ 160.06, 151.34, 146.73, 145.01, 138.54, 136.81, 135.28, 131.28, 130.08, 129.58, 126.09, 122.59, 121.72, 119.14, 118.93, 114.82, 111.78, 110.70, 109.62, 56.19.
Figure PCTCN2019090131-appb-000036
Figure PCTCN2019090131-appb-000036
N-(2-((3-((3-甲氧基苯基)亚磺酰基)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(3)：合成方法同化合物2。N- (2-((3-((3-methoxyphenyl) sulfinyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (3 ): The synthetic method is the same as that of compound 2.
1H NMR(400MHz,DMSO-d6)δ12.03(d,J＝2.9Hz,1H),9.68(s,1H),8.19(s,1H),7.87(d,J＝2.8Hz,1H),7.73(dd,J＝8.3,1.5Hz,1H),7.66-7.58(m,1H),7.45-7.37(m,2H),7.23(dd,J＝2.6,1.5Hz,1H),7.18-7.09(m,2H),7.09-6.99(m,2H),6.55(d,J＝8.7Hz,1H),6.47(dd,J＝17.0,10.2Hz,1H),6.22(dd,J＝17.0,2.0Hz,1H),5.71(dd,J＝10.1,2.0Hz,1H),3.78(s,3H).13C NMR(101MHz,DMSO)δ164.17,160.20,153.71,148.30,147.22,134.24,132.44,130.72,130.41,129.83,127.43,127.20,125.72,125.21,123.68,123.32,116.94,116.61,116.21,109.87,108.63,106.31,55.95.1HNMR (400MHz, DMSO-d6) δ12.03 (d, J = 2.9Hz, 1H), 9.68 (s, 1H), 8.19 (s, 1H), 7.87 (d, J = 2.8Hz, 1H), 7.73 (dd, J = 8.3, 1.5 Hz, 1H), 7.66-7.58 (m, 1H), 7.45-7.37 (m, 2H), 7.23 (dd, J = 2.6, 1.5Hz, 1H), 7.18-7.09 (m , 2H), 7.09-6.99 (m, 2H), 6.55 (d, J = 8.7 Hz, 1H), 6.47 (dd, J = 17.0, 10.2 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.71 (dd, J = 10.1, 2.0 Hz, 1H), 3.78 (s, 3H). 13C NMR (101MHz, DMSO) δ164.17, 160.20, 153.71, 148.30, 147.22, 134.24, 132.44, 130.72, 130.41, 129.83 , 127.43, 127.20, 125.72, 125.21, 123.68, 123.32, 116.94, 116.61, 116.21, 109.87, 108.63, 106.31, 55.95.
Figure PCTCN2019090131-appb-000037
Figure PCTCN2019090131-appb-000037
N-(2-((3-((3-甲氧基苯基)磺酰基)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(4)：合成方法同化合物2。白色固体16mg，产率42％。N- (2-((3-((3-methoxyphenyl) sulfonyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (4) ： Synthetic method is the same as that of compound 2. 16 mg of white solid, 42% yield.
1H NMR(400MHz,DMSO-d 6)δ12.37(d,J＝3.0Hz,1H),9.69(s,1H),8.31(s,1H),7.97(d,J＝8.6Hz,1H),7.92(d,J＝3.0Hz,1H),7.75(dd,J＝8.1,1.5Hz,1H),7.64(d,J＝8.0Hz,1H),7.56-7.46(m,2H),7.44(dd,J＝2.6,1.6Hz,1H),7.22-7.13(m,2H),7.07(td,J＝7.6,1.6Hz,1H),6.78(d,J＝8.7Hz,1H),6.49(dd,J＝17.0,10.2Hz,1H),6.24 (dd,J＝17.0,2.0Hz,1H),5.72(dd,J＝10.2,2.0Hz,1H),3.81(s,3H). 13C NMR(101MHz,DMSO)δ164.17,160.01,154.10,147.54,145.21,134.07,132.42,131.22,130.56,129.62,128.14,127.20,125.73,125.21,123.81,123.51,118.99,118.85,114.64,111.70,108.91,107.50,56.18.HRMS(ESI)m/z C 23H 20N 4O 4S[M+H] +的计算值448.1205；实测值449.1279. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.37 (d, J = 3.0 Hz, 1H), 9.69 (s, 1H), 8.31 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H) , 7.92 (d, J = 3.0 Hz, 1H), 7.75 (dd, J = 8.1, 1.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56-7.46 (m, 2H), 7.44 ( dd, J = 2.6, 1.6Hz, 1H), 7.22-7.13 (m, 2H), 7.07 (td, J = 7.6, 1.6Hz, 1H), 6.78 (d, J = 8.7Hz, 1H), 6.49 (dd , J = 17.0,10.2Hz, 1H), 6.24 (dd, J = 17.0,2.0Hz, 1H), 5.72 (dd, J = 10.2,2.0Hz, 1H), 3.81 (s, 3H). 13 C NMR ( (101MHz, DMSO) δ164.17, 160.01, 154.10, 147.54, 145.21, 134.07, 132.42, 131.22, 130.56, 129.62, 128.14, 127.20, 125.73, 125.21, 123.81, 123.51, 118.99, 118.85, 114.64, 111.70, 108.91, 107.50, 56.18. HRMS (ESI) m / z Calculated value for C 23 H 20 N 4 O 4 S [M + H] + 44.1205; found 449.1279.
Figure PCTCN2019090131-appb-000038
Figure PCTCN2019090131-appb-000038
条件和试剂：Conditions and reagents:
(a)NIS,DMF,室温,1h；(a) NIS, DMF, room temperature, 1h;
(b)Boc 2O,DMAP,DCM,室温； (b) Boc 2 O, DMAP, DCM, room temperature;
(c)1-乙炔基-3,5-二甲氧基苯,CuI,Pd(PPh 3) 2Cl 2,Et 3N,DCM,室温,16h； (c) 1-ethynyl-3,5-dimethoxybenzene, CuI, Pd (PPh 3 ) 2 Cl 2 , Et 3 N, DCM, room temperature, 16 h;
(d)2-硝基苯胺,Pd(AcO) 2,Xant-phos,Cs 2CO 3,1,4-二氧六环,100摄氏度,过夜； (d) 2-nitroaniline, Pd (AcO) 2 , Xant-phos, Cs 2 CO 3 , 1,4-dioxane, 100 degrees Celsius, overnight;
(e)SnCl 2,EtOAc,回流； (e) SnCl 2 , EtOAc, reflux;
(f)丙烯酰氯,DIEA,THF,0摄氏度,然后室温(f) Acryloyl chloride, DIEA, THF, 0 degrees Celsius, and then room temperature
Figure PCTCN2019090131-appb-000039
Figure PCTCN2019090131-appb-000039
条件和试剂：NIS,DMF,室温,1hConditions and reagents: NIS, DMF, room temperature, 1h
6-氯-3-碘-1H-吡咯并[2,3-b]吡啶(I14)：将化合物7-氮杂吲哚 (0.20g，1.3mmol)溶于无水DMF(5.0mL)，0℃搅拌下加入NIS(0.32g，1.4mmol)。反应液在室温下搅拌1h后，加水稀释，乙酸乙酯(3×80mL)萃取，收集有机相，食盐水(2×40mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.31g，产率85％。 1H NMR(400MHz,DMSO)δ12.33(s,1H),7.97-7.52(m,2H),7.19(d,J＝8.2Hz,1H). 13C NMR(101MHz,DMSO)δ147.23,144.70,131.80,131.76,121.64,116.80,55.24. 6-chloro-3-iodo-1H-pyrrolo [2,3-b] pyridine (I14): Compound 7-azaindole (0.20 g, 1.3 mmol) was dissolved in anhydrous DMF (5.0 mL), 0 Add NIS (0.32 g, 1.4 mmol) with stirring at ° C. The reaction solution was stirred at room temperature for 1 h, diluted with water, extracted with ethyl acetate (3 × 80 mL), and the organic phase was collected, washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a yellow solid. 0.31 g, yield 85%. 1 H NMR (400MHz, DMSO) δ 12.33 (s, 1H), 7.97-7.52 (m, 2H), 7.19 (d, J = 8.2Hz, 1H). 13 C NMR (101MHz, DMSO) δ 147.23, 144.70, 131.80, 131.76, 121.64, 116.80, 55.24.
Figure PCTCN2019090131-appb-000040
Figure PCTCN2019090131-appb-000040
条件和试剂：Boc 2O,DMAP,DCM,室温 Conditions and reagents: Boc 2 O, DMAP, DCM, room temperature
6-氯-3-碘-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I15)：将化合物I14(0.31g，1.1mmol)溶于DCM，依次加入Boc 2O(0.36g，0.38mL，1.7mmol)、DMAP(0.007g，0.056mmol)，室温搅拌2h后，浓缩，加水和乙酸乙酯萃取，收集有机相，食盐水(2×40mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.41g，产率96％。 1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.65(d,J＝8.2Hz,1H),7.29(d,J＝8.2Hz,1H),1.67(s,9H). 13C NMR(101MHz,CDCl 3)δ147.95,146.69,145.93,132.08,131.11,124.07,119.82,85.40,61.25,28.12. 6-Chloro-3-iodo-1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid tert-butyl ester (I15): Compound I14 (0.31 g, 1.1 mmol) was dissolved in DCM, and Boc 2 O was added sequentially. (0.36g, 0.38mL, 1.7mmol), DMAP (0.007g, 0.056mmol), stirred at room temperature for 2h, concentrated, extracted with water and ethyl acetate, collected the organic phase, washed with brine (2 × 40mL), anhydrous sulfuric acid Sodium was dried, concentrated, and purified by column chromatography to obtain 0.41 g of a yellow solid with a yield of 96%. 1 H NMR (400MHz, CDCl 3 ) δ 7.79 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 1.67 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 147.95, 146.69, 145.93, 132.08, 131.11, 124.07, 119.82, 85.40, 61.25, 28.12.
Figure PCTCN2019090131-appb-000041
Figure PCTCN2019090131-appb-000041
条件和试剂：CuI,Pd(PPh 3) 2Cl 2,Et 3N,DCM,室温,16h Conditions and reagents: CuI, Pd (PPh 3 ) 2 Cl 2 , Et 3 N, DCM, room temperature, 16h
6-氯-3-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I16)：将化合物I15(0.10g，0.26mmol)、3,5-二甲氧基苯乙炔(0.047g，0.29mmol)、Pd(PPh 3) 2Cl 2(0.018g，0.026mmol)、 CuI(0.010g，0.052mmol)、Et 3N(0.031g，43μL，0.32mmol)溶于无水二氯甲烷(3.0mL)，通入氩气除氧。反应液在室温下搅拌16h，冷却至室温，过滤，往滤液中加入水(20mL)和二氯甲烷(3×20mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.074g，产率69％。 1H NMR(500MHz,氯仿-d)δ8.00(d,J＝8.1Hz,1H),7.88(s,1H),7.31(d,J＝8.2Hz,1H),6.70(d,J＝2.3Hz,2H),6.49(t,J＝2.2Hz,1H),3.82(s,6H),1.69(s,8H).MS(ESI):413[M+H] +. 6-Chloro-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid tert-butyl ester (I16): Compound I15 ( 0.10 g, 0.26 mmol), 3,5-dimethoxyphenylacetylene (0.047 g, 0.29 mmol), Pd (PPh 3 ) 2 Cl 2 (0.018 g, 0.026 mmol), CuI (0.010 g, 0.052 mmol), Et 3 N (0.031 g, 43 μL, 0.32 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), and argon was passed to remove oxygen. The reaction solution was stirred at room temperature for 16h, cooled to room temperature, and filtered. Water (20mL) and dichloromethane (3 × 20mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography gave 0.074 g of a yellow solid with a yield of 69%. 1 H NMR (500MHz, chloroform-d) δ8.00 (d, J = 8.1Hz, 1H), 7.88 (s, 1H), 7.31 (d, J = 8.2Hz, 1H), 6.70 (d, J = 2.3 Hz, 2H), 6.49 (t, J = 2.2Hz, 1H), 3.82 (s, 6H), 1.69 (s, 8H) .MS (ESI): 413 [M + H] + .
Figure PCTCN2019090131-appb-000042
Figure PCTCN2019090131-appb-000042
条件和试剂：Pd(AcO) 2,Xant-phos,Cs 2CO 3,1,4-二氧六环,100摄氏度,过夜 Conditions and reagents: Pd (AcO) 2 , Xant-phos, Cs 2 CO 3 , 1,4-dioxane, 100 ° C, overnight
3-((3,5-二甲氧基苯基)乙炔基)-6-((2-硝基苯基)氨基)-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I17)：将化合物I16(0.074g，0.18mmol)、2-硝基苯胺(0.027g，0.20mmol)、Pd(OAc) 2(0.004g，0.018mmol)、Xant-Phos(0.021g，0.036mmol)、碳酸铯(0.12g，0.36mmol)溶于无水1,4-二氧六环(4.0mL)，通入氩气除氧。反应液在100℃条件下搅拌过夜，冷却至室温，过滤，往滤液中加入水(20mL)和乙酸乙酯(3×20mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.045g，产率48％。 1H NMR(400MHz,氯仿-d)δ10.60(s,1H),9.32(dd,J＝8.8,1.3Hz,1H),8.26(dd,J＝8.6,1.6Hz,1H),7.99(d,J＝8.4Hz,1H),7.80(s,1H),7.66(ddd,J＝8.7,7.1,1.7Hz,1H),7.00-6.97(m,1H),6.94(d,J＝8.4Hz,1H),6.72(d,J＝2.3Hz,2H),6.49(t,J＝2.3Hz,1H),3.82(s,6H),1.69(s,9H). 13C NMR(101MHz,CDCl 3)δ160.70,150.82,147.58,145.50,139.17,136.33,134.49,130.76,127.94,126.33,124.40,119.82,119.64,117.84,110.29,109.46,101.96,101.11,92.76,84.74,80.32,55.55,28.30. 3-((3,5-dimethoxyphenyl) ethynyl) -6-((2-nitrophenyl) amino) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid tert Butyl ester (I17): Compound I16 (0.074 g, 0.18 mmol), 2-nitroaniline (0.027 g, 0.20 mmol), Pd (OAc) 2 (0.004 g, 0.018 mmol), Xant-Phos (0.021 g, 0.036 mmol), cesium carbonate (0.12 g, 0.36 mmol) was dissolved in anhydrous 1,4-dioxane (4.0 mL), and argon was passed to remove oxygen. The reaction solution was stirred at 100 ° C overnight, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 x 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.045 g of a yellow solid with a yield of 48%. 1 H NMR (400MHz, chloroform-d) δ 10.60 (s, 1H), 9.32 (dd, J = 8.8, 1.3 Hz, 1H), 8.26 (dd, J = 8.6, 1.6 Hz, 1H), 7.99 (d , J = 8.4Hz, 1H), 7.80 (s, 1H), 7.66 (ddd, J = 8.7, 7.1, 1.7Hz, 1H), 7.00-6.97 (m, 1H), 6.94 (d, J = 8.4Hz, 1H), 6.72 (d, J = 2.3Hz, 2H), 6.49 (t, J = 2.3Hz, 1H), 3.82 (s, 6H), 1.69 (s, 9H). 13 C NMR (101MHz, CDCl 3 ) δ 160.70, 150.82, 147.58, 145.50, 139.17, 136.33, 134.49, 130.76, 127.94, 126.33, 124.40, 119.82, 119.64, 117.84, 110.29, 109.46, 101.96, 101.11, 92.76, 84.74, 80.32, 55.55, 28.30.
Figure PCTCN2019090131-appb-000043
Figure PCTCN2019090131-appb-000043
条件和试剂：SnCl 2,EtOAc,回流 Conditions and reagents: SnCl 2 , EtOAc, reflux
N 1-(3-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-6-基)苯-1,2-二胺(I18)：将化合物I17(0.045g，0.087mmol)溶于乙酸乙酯，加入SnCl 2(0.084g，0.44mmol)，回流搅拌2h，冷却至室温，加入饱和碳酸氢钠水溶于淬灭反应，过滤，往滤液中加入乙酸乙酯萃取，收集有机相，水洗，饱和食盐水洗涤，浓缩得到中间体I9(37mg)，不需经过纯化可直接用于下一步反应。MS(ESI):385[M+H] +. N 1- (3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) benzene-1,2-diamine (I18 ): Compound I17 (0.045 g, 0.087 mmol) was dissolved in ethyl acetate, SnCl 2 (0.084 g, 0.44 mmol) was added, stirred at reflux for 2 h, cooled to room temperature, saturated sodium bicarbonate water was added to dissolve the quenching reaction, and filtered, Ethyl acetate was added to the filtrate for extraction, and the organic phase was collected, washed with water, saturated brine, and concentrated to obtain intermediate I9 (37 mg), which was directly used in the next reaction without purification. MS (ESI): 385 [M + H] + .
Figure PCTCN2019090131-appb-000044
Figure PCTCN2019090131-appb-000044
条件和试剂：DIEA,THF,0摄氏度,然后室温Conditions and reagents: DIEA, THF, 0 ° C, then room temperature
N-(2-((3-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(5)：将化合物I18(37mg，0.098mmol)溶于四氢呋喃(2.0mL)，冰水浴条件下，依次加入DIEA(33μL，0.20mmol)和丙烯酰氯(9.5μL，0.12mmol)，室温反应30min。浓缩后加入水(10mL)和乙酸乙酯(3×10mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体10mg，产率23％。 1H NMR(500MHz,DMSO-d 6)δ11.68(d,J＝2.7Hz,1H),9.76(s,1H),8.19(s,1H),7.88(d,J＝8.5Hz,1H),7.84(d,J＝8.0Hz,1H), 7.61(d,J＝8.0Hz,1H),7.51(d,J＝2.4Hz,1H),7.20-7.14(m,1H),7.04(td,J＝7.6,1.5Hz,1H),6.73(d,J＝8.5Hz,1H),6.68(d,J＝2.3Hz,2H),6.54-6.44(m,2H),6.24(dd,J＝17.1,1.9Hz,1H),5.73(dd,J＝10.2,2.0Hz,1H),3.77(s,6H).MS(ESI):439[M+H] +. N- (2-((3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (5): Compound I18 (37 mg, 0.098 mmol) was dissolved in tetrahydrofuran (2.0 mL), and DIEA (33 μL, 0.20 mmol) and acryloyl chloride (9.5 μL, 0.12 mmol) were sequentially added under an ice water bath condition, and the reaction was performed at room temperature for 30 min. After concentration, water (10 mL) and ethyl acetate (3 × 10 mL) were added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 10 mg of a white solid with a yield of 23%. 1 H NMR (500MHz, DMSO-d 6 ) δ 11.68 (d, J = 2.7 Hz, 1H), 9.76 (s, 1H), 8.19 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.20-7.14 (m, 1H), 7.04 (td, J = 7.6, 1.5Hz, 1H), 6.73 (d, J = 8.5Hz, 1H), 6.68 (d, J = 2.3Hz, 2H), 6.54-6.44 (m, 2H), 6.24 (dd, J = 17.1 , 1.9Hz, 1H), 5.73 (dd, J = 10.2, 2.0Hz, 1H), 3.77 (s, 6H) .MS (ESI): 439 [M + H] + .
Figure PCTCN2019090131-appb-000045
Figure PCTCN2019090131-appb-000045
条件和试剂：Conditions and reagents:
(a)TFA,Et 3SiH,CH3CN,室温,2h； (a) TFA, Et 3 SiH, CH3CN, room temperature, 2h;
(b)NaH,SEM-Cl,0摄氏度,然后室温；(b) NaH, SEM-Cl, 0 degrees Celsius, and then room temperature;
(c)2-硝基苯胺,Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜； (c) 2-nitroaniline, Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 degrees Celsius, overnight;
(d)SnCl 2,EtOAc,回流； (d) SnCl 2 , EtOAc, reflux;
(e)丙烯酰氯,DIEA,THF,0摄氏度,然后室温(e) Acryloyl chloride, DIEA, THF, 0 degrees Celsius, and then room temperature
Figure PCTCN2019090131-appb-000046
Figure PCTCN2019090131-appb-000046
条件和试剂：TFA,Et 3SiH,CH3CN,室温,2h Conditions and reagents: TFA, Et 3 SiH, CH3CN, room temperature, 2h
6-氯-3-(3,5-二甲氧基苄基)-1H-吡咯并[2,3-b]吡啶(I19)：将化合物I24b(0.50g，1.5mmol)溶于乙腈(20mL)，加入三氟乙酸(0.67mL，9.0mmol)和Et 3SiH(0.74mL，6.0mmol)。室温搅拌2h后，加入饱和碳酸氢钠水溶液(50mL)淬灭反应，加入乙酸乙酯(3×50mL)萃取，收集有机相用饱和食盐水洗涤(3×30mL)，无水硫酸钠 干燥，浓缩，柱层析分离纯化得到白色固体0.11g，产率24％。MS(ESI):303[M+H] +. 6-chloro-3- (3,5-dimethoxybenzyl) -1H-pyrrolo [2,3-b] pyridine (I19): Compound I24b (0.50 g, 1.5 mmol) was dissolved in acetonitrile (20 mL ), Trifluoroacetic acid (0.67 mL, 9.0 mmol) and Et 3 SiH (0.74 mL, 6.0 mmol) were added. After stirring at room temperature for 2h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (50mL), and extracted with ethyl acetate (3 × 50mL). The organic phase was collected and washed with saturated brine (3 × 30mL), dried over anhydrous sodium sulfate, and concentrated. The column chromatography separated and purified to obtain 0.11 g of a white solid with a yield of 24%. MS (ESI): 303 [M + H] + .
化合物6的其余合成步骤b-d与化合物5类似。The remaining synthetic steps b-d of compound 6 are similar to those of compound 5.
Figure PCTCN2019090131-appb-000047
Figure PCTCN2019090131-appb-000047
条件和试剂：DIEA,THF,0摄氏度,然后室温Conditions and reagents: DIEA, THF, 0 ° C, then room temperature
N-(2-((3-(3,5-二甲氧基苄基)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(6)：白色固体8mg，产率19％。 1H NMR(400MHz,DMSO-d 6)δ10.95(d,J＝2.3Hz,1H),9.81(s,1H),7.97(s,1H),7.77(d,J＝8.0Hz,1H),7.62(d,J＝8.4Hz,1H),7.55(d,J＝7.9Hz,1H),7.16-7.09(m,1H),6.99(td,J＝7.6,1.5Hz,1H),6.91(d,J＝2.3Hz,1H),6.54(d,J＝8.5Hz,1H),6.49-6.37(m,3H),6.28(t,J＝2.3Hz,1H),6.22(dd,J＝17.0,2.0Hz,1H),5.71(dd,J＝10.1,2.0Hz,1H),3.86(s,2H),3.67(s,6H). 13C NMR(101MHz,DMSO)δ164.12,160.88,152.22,147.57,144.52,135.37,132.49,129.55,127.13,125.82,125.38,122.48,122.42,119.97,113.49,113.03,107.13,104.18,97.91,55.55,32.08.HRMS(ESI)m/z C 25H 24N 4O 3[M+H] +的计算值428.4920；实测值429.1924. N- (2-((3- (3,5-dimethoxybenzyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (6): 8 mg white solid, 19% yield. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.95 (d, J = 2.3 Hz, 1H), 9.81 (s, 1H), 7.97 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H) , 7.62 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.16-7.09 (m, 1H), 6.99 (td, J = 7.6, 1.5 Hz, 1H), 6.91 ( d, J = 2.3Hz, 1H), 6.54 (d, J = 8.5Hz, 1H), 6.49-6.37 (m, 3H), 6.28 (t, J = 2.3Hz, 1H), 6.22 (dd, J = 17.0 , 2.0Hz, 1H), 5.71 (dd, J = 10.1, 2.0Hz, 1H), 3.86 (s, 2H), 3.67 (s, 6H). 13 C NMR (101MHz, DMSO) δ164.12, 160.88, 152.22, 147.57 , 144.52,135.37,132.49,129.55,127.13,125.82,125.38,122.48,122.42,119.97,113.49,113.03,107.13,104.18,97.91,55.55,32.08.HRMS (ESI) m / z C 25 H 24 N 4 O 3 [M + H] + Calculated 428.4920; Found 429.1924.
Figure PCTCN2019090131-appb-000048
Figure PCTCN2019090131-appb-000048
对于I24-I29和产物来说，R1＝3-甲氧基，3,5-二氧基，或2,6-二 氯-3,5-二氧基；R 2＝H或CH3. For I24-I29 and products, R1 = 3-methoxy, 3,5-dioxy, or 2,6-dichloro-3,5-dioxy; R 2 = H or CH3.
条件和试剂：Conditions and reagents:
(a)ArCHO,KOH,MeOH,过夜；(a) ArCHO, KOH, MeOH, overnight;
(b)DDQ,H2O/1,4-二氧六环,室温,2h；(b) DDQ, H2O / 1,4-dioxane, room temperature, 2h;
(c)NaH,SEM-Cl,0摄氏度,然后室温；(c) NaH, SEM-Cl, 0 degrees Celsius, and then room temperature;
(d)2-硝基苯胺或2-甲基-6-硝基苯胺,Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜； (d) 2-nitroaniline or 2-methyl-6-nitroaniline, Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 degrees Celsius, overnight;
(e)i)TFA,DCM,室温；ii)K 2CO 3,MeOH,室温； (e) i) TFA, DCM, room temperature; ii) K 2 CO 3 , MeOH, room temperature;
(f)H 2,Pd/C,EtOAc,室温或SnCl 2,EA,回流； (f) H 2 , Pd / C, EtOAc, room temperature or SnCl 2 , EA, reflux;
(g)丙烯酰氯,DIEA,THF,0摄氏度,然后室温.(g) Acryloyl chloride, DIEA, THF, 0 degrees Celsius, and then room temperature.
Figure PCTCN2019090131-appb-000049
Figure PCTCN2019090131-appb-000049
条件和试剂：KOH,MeOH,室温Conditions and reagents: KOH, MeOH, room temperature
(6-氯-1H-吡咯并[2,3-b]吡啶-3-基)(3,5-二甲氧基苯基)甲醇(I24b)：将6-氯-7-氮杂吲哚(2.0g，13mmol)溶于甲醇(65mL)，依次加入氢氧化钾(2.9g，52mmol)，3，5-二甲氧基苯甲醛(2.4g，14mmol)。反应液室温搅拌过夜，TLC监测反应结束后，加入4N的盐酸调节pH至7，浓缩后加入乙酸乙酯(3×200mL)和水萃取，收集有机相用饱和食盐水洗涤(3×80mL)，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体3.7g，产率89％。 1H NMR(500MHz,DMSO)δ11.66(s,1H),7.89(d,J＝8.2Hz,1H),7.30(d,J＝2.3Hz,1H),7.04(d,J＝8.2Hz,1H),6.61(d,J＝2.2Hz,2H),6.34(t,J＝2.3Hz,1H),5.84(d,J＝4.5Hz,1H),5.75(d,J＝4.5Hz,1H),3.69(s,6H). 13C NMR(126MHz,DMSO)δ160.69,148.22,148.00,143.35,131.32,123.94,119.27,117.25,115.17,104.81,98.84,69.11,55.54. (6-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) (3,5-dimethoxyphenyl) methanol (I24b): 6-chloro-7-azaindole (2.0 g, 13 mmol) was dissolved in methanol (65 mL), and potassium hydroxide (2.9 g, 52 mmol), 3,5-dimethoxybenzaldehyde (2.4 g, 14 mmol) were added in this order. The reaction solution was stirred overnight at room temperature. After the reaction was monitored by TLC, 4N hydrochloric acid was added to adjust the pH to 7. After concentration, ethyl acetate (3 × 200 mL) and water were added for extraction. The organic phase was collected and washed with saturated brine (3 × 80 mL). It was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 3.7 g of a white solid with a yield of 89%. 1 H NMR (500MHz, DMSO) δ 11.66 (s, 1H), 7.89 (d, J = 8.2Hz, 1H), 7.30 (d, J = 2.3Hz, 1H), 7.04 (d, J = 8.2Hz, 1H), 6.61 (d, J = 2.2Hz, 2H), 6.34 (t, J = 2.3Hz, 1H), 5.84 (d, J = 4.5Hz, 1H), 5.75 (d, J = 4.5Hz, 1H) , 3.69 (s, 6H). 13 C NMR (126MHz, DMSO) δ 160.69, 148.22, 148.00, 143.35, 131.32, 123.94, 119.27, 117.25, 115.17, 104.81, 98.84, 69.11, 55.54.
Figure PCTCN2019090131-appb-000050
Figure PCTCN2019090131-appb-000050
条件和试剂：DDQ,1,4-二氧六环/H2O,室温,2hConditions and reagents: DDQ, 1,4-dioxane / H2O, room temperature, 2h
(6-氯-1H-吡咯并[2,3-b]吡啶-3-基)(3,5-二甲氧基苯基)甲酮(I25b)：将化合物I24b(0.65g，2.0mmol)溶于1,4-二氧六环(20mL)，依次加入DDQ(0.74g，3.3mmol)和水(0.80mL)。室温搅拌2h后，加入饱和碳酸氢钠水溶液(50mL)淬灭反应，加入乙酸乙酯(3×50mL)萃取，收集有机相用饱和食盐水洗涤(3×30mL)，无水硫酸钠干燥，浓缩，柱层析分离纯化得到白色固体0.51g，产率81％。 1H NMR(400MHz,DMSO)δ12.82(s,1H),8.52(d,J＝8.2Hz,1H),8.22(d,J＝2.9Hz,1H),7.37(d,J＝8.2Hz,1H),6.91(d,J＝2.3Hz,2H),6.74(t,J＝2.3Hz,1H),3.81(s,6H). 13C NMR(101MHz,DMSO)δ189.81,160.89,148.52,145.24,141.84,136.83,133.35,118.68,118.15,114.25,106.81,104.11,55.99. (6-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) (3,5-dimethoxyphenyl) methanone (I25b): Compound I24b (0.65 g, 2.0 mmol) It was dissolved in 1,4-dioxane (20 mL), and DDQ (0.74 g, 3.3 mmol) and water (0.80 mL) were added in this order. After stirring at room temperature for 2h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (50mL), and extracted with ethyl acetate (3 × 50mL). The organic phase was collected and washed with saturated brine (3 × 30mL), dried over anhydrous sodium sulfate, and concentrated. The column chromatography separated and purified to obtain 0.51 g of a white solid with a yield of 81%. 1 H NMR (400MHz, DMSO) δ 12.82 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 2.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 2.3Hz, 2H), 6.74 (t, J = 2.3Hz, 1H), 3.81 (s, 6H). 13 C NMR (101MHz, DMSO) δ189.81, 160.89, 148.52, 145.24, 141.84,136.83,133.35,118.68,118.15,114.25,106.81,104.11,55.99.
Figure PCTCN2019090131-appb-000051
Figure PCTCN2019090131-appb-000051
条件和试剂：NaH,SEM-Cl,0摄氏度,然后室温Conditions and reagents: NaH, SEM-Cl, 0 ° C, then room temperature
(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)(3,5-二甲氧基苯基)甲酮(I26b)：将化合物I25b(0.38g，1.2mmol)溶于无水DMF(5.0mL)，0℃搅拌下加入60％氢化钠(0.073g，1.8mmol)。反应液在0℃下搅拌30min后，加入SEM-Cl(0.31g，0.32mL，1.8mmol)，升至室温搅拌2h。TLC监测反应完全后，加水(50mL)稀释，乙酸乙酯(3×50mL)萃取，收集有机相用饱和食盐水洗涤(3×20mL)，无水硫酸钠干燥，浓缩，柱层析纯化得到无色油状液体0.35g，产率78％。 1H NMR(400MHz,CDCl 3)δ8.65-8.53(m,1H),7.87(s,1H),7.33-7.27(m,1H),6.94(d,J＝2.3Hz,2H), 6.65(t,J＝2.3Hz,1H),5.66(s,2H),3.83(s,6H),3.64-3.55(m,2H),0.98-0.87(m,2H),-0.06(s,9H). 13C NMR(101MHz,CDCl 3)δ190.26,160.88,147.71,146.80,141.39,135.92,133.67,119.42,118.13,115.34,106.77,103.86,73.53,67.28,55.68,17.82,-1.41. (6-chloro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (3,5-di Methoxyphenyl) methanone (I26b): Compound I25b (0.38 g, 1.2 mmol) was dissolved in anhydrous DMF (5.0 mL), and 60% sodium hydride (0.073 g, 1.8 mmol) was added with stirring at 0 ° C. After the reaction solution was stirred at 0 ° C for 30 min, SEM-Cl (0.31 g, 0.32 mL, 1.8 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. After the reaction was monitored by TLC, it was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was collected and washed with saturated brine (3 × 20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography. 0.35 g of a color oily liquid with a yield of 78%. 1 H NMR (400MHz, CDCl 3 ) δ8.65-8.53 (m, 1H), 7.87 (s, 1H), 7.33-7.27 (m, 1H), 6.94 (d, J = 2.3Hz, 2H), 6.65 ( t, J = 2.3Hz, 1H), 5.66 (s, 2H), 3.83 (s, 6H), 3.64-3.55 (m, 2H), 0.98-0.87 (m, 2H), -0.06 (s, 9H). 13 C NMR (101MHz, CDCl 3 ) δ190.26,160.88,147.71,146.80,141.39,135.92,133.67,119.42,118.13,115.34,106.77,103.86,73.53,67.28,55.68,17.82, -1.41.
Figure PCTCN2019090131-appb-000052
Figure PCTCN2019090131-appb-000052
条件和试剂：Pd 2(dba) 3,X-phos,K 2CO 3,1,4-二氧六环,110摄氏度,过夜 Conditions and reagents: Pd 2 (dba) 3 , X-phos, K 2 CO 3 , 1,4-dioxane, 110 ° C, overnight
(3,5-二甲氧基苯基)(6-((2-甲基-6-硝基苯基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(I27d)：将化合物I26b(0.18g，0.41mmol)、2-甲基-6-硝基苯胺(0.069g，0.45mmol)、Pd 2(dba) 3(0.038g，0.041mmol)、X-Phos(0.039g，0.082mmol)、碳酸钾(0.11g，0.82mmol)溶于无水1,4-二氧六环(4.0mL)，通入氩气除氧。反应液在110℃条件下搅拌6h，冷却至室温，过滤，往滤液中加入水(20mL)和乙酸乙酯(3×20mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.16g，产率69％。 1H NMR(400MHz,CDCl 3)δ8.46(dd,J＝8.5,4.3Hz,1H),8.03(s,1H),7.92(dd,J＝8.3,1.1Hz,1H),7.65(s,1H),7.50(d,J＝7.0Hz,1H),7.22-7.16(m,1H),6.95(d,J＝2.3Hz,2H),6.66-6.60(m,2H),5.46(s,2H),3.84(s,6H),3.51-3.45(m,2H),2.26(s,3H),0.87-0.81(m,2H),-0.07--0.11(m,9H). 13C NMR(101MHz,CDCl 3)δ190.54,160.75,152.07,147.44,144.29,141.87,136.52,136.17,134.10,133.96,133.24,123.87,123.40,115.71,113.41,107.30,106.72,103.67,73.32,66.87,55.65,19.58,17.83,-1.42. (3,5-dimethoxyphenyl) (6-((2-methyl-6-nitrophenyl) amino) -1-((2- (trimethylsilyl) ethoxy) (Methyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) methanone (I27d): Compound I26b (0.18 g, 0.41 mmol), 2-methyl-6-nitroaniline (0.069 g, 0.45 mmol), Pd 2 (dba) 3 (0.038 g, 0.041 mmol), X-Phos (0.039 g, 0.082 mmol), potassium carbonate (0.11 g, 0.82 mmol) dissolved in anhydrous 1,4-dioxy Six rings (4.0 mL) were purged with argon to remove oxygen. The reaction solution was stirred at 110 ° C. for 6 h, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 × 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.16 g of a yellow solid with a yield of 69%. 1 H NMR (400MHz, CDCl 3 ) δ 8.46 (dd, J = 8.5, 4.3 Hz, 1H), 8.03 (s, 1H), 7.92 (dd, J = 8.3, 1.1 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J = 7.0Hz, 1H), 7.22-7.16 (m, 1H), 6.95 (d, J = 2.3Hz, 2H), 6.66-6.60 (m, 2H), 5.46 (s, 2H ), 3.84 (s, 6H), 3.51-3.45 (m, 2H), 2.26 (s, 3H), 0.87-0.81 (m, 2H), -0.07--0.11 (m, 9H). 13 C NMR (101MHz , CDCl 3 ) δ190.54,160.75,152.07,147.44,144.29,141.87,136.52,136.17,134.10,133.96,133.24,123.87,123.40,115.71,113.41,107.30,106.72,103.67,73.32,66.87,55.65,19.58,17.83,83.83 -1.42.
Figure PCTCN2019090131-appb-000053
Figure PCTCN2019090131-appb-000053
条件和试剂：i)TFA,DCM,室温；ii)K 2CO 3,MeOH,室温 Conditions and reagents: i) TFA, DCM, room temperature; ii) K 2 CO 3 , MeOH, room temperature
(3,5-二甲氧基苯基)(6-((2-甲基-6-硝基苯基)氨基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(I28d)：将化合物I27d(0.12g，0.21mmol)溶于二氯甲烷(2.0mL)，加入三氟乙酸(2.0mL)。反应液在室温搅拌5h，浓缩后得到的固体溶于甲醇(2.0mL)后加入碳酸钾调节pH至12，室温搅拌过夜。TLC监测反应结束后，浓缩，加入水(20mL)和乙酸乙酯(3×20mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体39mg，产率43％。 1H NMR(400MHz,CDCl 3)δ10.60(s,1H),8.54(d,J＝8.5Hz,1H),8.24(s,1H),7.82(dd,J＝8.3,1.0Hz,1H),7.41(d,J＝7.1Hz,1H),7.11(d,J＝2.9Hz,1H),7.10-7.04(m,1H),6.91(d,J＝2.3Hz,2H),6.71(d,J＝8.5Hz,1H),6.69-6.66(m,1H),3.86(s,6H),2.24(s,3H). 13C NMR(101MHz,CDCl 3)δ190.64,160.80,151.87,147.41,144.07,141.84,136.72,136.48,133.92,133.81,131.68,124.14,123.61,115.81,113.47,107.77,106.67,103.53,55.68,19.76. (3,5-dimethoxyphenyl) (6-((2-methyl-6-nitrophenyl) amino) -1H-pyrrolo [2,3-b] pyridin-3-yl) methyl Ketone (I28d): Compound I27d (0.12 g, 0.21 mmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added. The reaction solution was stirred at room temperature for 5 h. The solid obtained after concentration was dissolved in methanol (2.0 mL), potassium carbonate was added to adjust the pH to 12, and the mixture was stirred at room temperature overnight. After the reaction was monitored by TLC, the reaction solution was concentrated and extracted by adding water (20 mL) and ethyl acetate (3 × 20 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 39 mg of a yellow solid. Yield: 43%. 1 H NMR (400MHz, CDCl 3 ) δ 10.60 (s, 1H), 8.54 (d, J = 8.5Hz, 1H), 8.24 (s, 1H), 7.82 (dd, J = 8.3, 1.0Hz, 1H) , 7.41 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.10-7.04 (m, 1H), 6.91 (d, J = 2.3 Hz, 2H), 6.71 (d, J = 8.5Hz, 1H), 6.69-6.66 (m, 1H), 3.86 (s, 6H), 2.24 (s, 3H). 13 C NMR (101MHz, CDCl 3 ) δ190.64, 160.80, 151.87, 147.41, 144.07, 141.84,136.72,136.48,133.92,133.81,131.68,124.14,123.61,115.81,113.47,107.77,106.67,103.53,55.68,19.76.
Figure PCTCN2019090131-appb-000054
Figure PCTCN2019090131-appb-000054
条件和试剂：H2,Pd/C,EtOAc,室温Conditions and reagents: H2, Pd / C, EtOAc, room temperature
(6-((2-氨基-6-甲基苯基)氨基)-1H-吡咯并[2,3-b]吡啶-3-基)(3,5-二甲氧基苯基)甲酮(I29d)：将化合物I28d(39mg，0.090mmol)溶于乙酸乙酯，加入10％Pd/C，氢气(1atm)还原室温搅拌过夜，过滤，收集滤液，浓缩得到白色固体中间体I29d(29mg)，不需经过纯化可直接用于下一步反应。(6-((2-amino-6-methylphenyl) amino) -1H-pyrrolo [2,3-b] pyridin-3-yl) (3,5-dimethoxyphenyl) methanone (I29d): Compound I28d (39 mg, 0.090 mmol) was dissolved in ethyl acetate, 10% Pd / C was added, and hydrogen (1 atm) was reduced at room temperature and stirred overnight. The filtrate was collected and concentrated to give a white solid intermediate I29d (29 mg). It can be directly used in the next step without purification.
Figure PCTCN2019090131-appb-000055
Figure PCTCN2019090131-appb-000055
条件和试剂：DIEA,THF,0摄氏度,然后室温Conditions and reagents: DIEA, THF, 0 ° C, then room temperature
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-3-甲基苯基)丙烯酰胺(10)：将化合物I29d(29mg，0.072mmol)溶于四氢呋喃(2.0mL)，冰水浴条件下，依次加入DIEA(7.0μL，0.087mmol)和丙烯酰氯(24μL，0.14mmol)，室温反应30min。浓缩后加入水(10mL)和乙酸乙酯(3×10mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体16mg，产率49％。 1H NMR(400MHz,DMSO-d 6)δ12.07(d,J＝2.8Hz,1H),9.45(s,1H),8.20(d,J＝8.5Hz,1H),7.89(s,1H),7.77(d,J＝8.0Hz,1H),7.62(d,J＝2.7Hz,1H),7.15(t,J＝7.8Hz,1H),7.11-7.00(m,1H),6.83(d,J＝2.3Hz,2H),6.69(t,J＝2.3Hz,1H),6.56-6.40(m,2H),6.17(dd,J＝17.0,2.0Hz,1H),5.65(dd,J＝10.2,2.0Hz,1H),3.78(s,6H),2.14(s,3H). 13C NMR(101MHz,DMSO)δ189.71,163.92,160.76,155.45,148.77,142.52,137.24,135.88,132.53,132.08,131.63,127.24,127.08,126.20,121.20,114.83,110.98,106.69,105.73,103.59,55.94,19.02.HRMS(ESI)m/z C 26H 24N 4O 4[M+H] +的计算值456.1798；实测值457.1868. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -3-methylphenyl) Acrylamide (10): Compound I29d (29 mg, 0.072 mmol) was dissolved in tetrahydrofuran (2.0 mL), and DIEA (7.0 μL, 0.087 mmol) and acryloyl chloride (24 μL, 0.14 mmol) were sequentially added under ice-water bath conditions, and reacted at room temperature. 30min. After concentration, water (10 mL) and ethyl acetate (3 × 10 mL) were added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 16 mg of a white solid with a yield of 49%. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.07 (d, J = 2.8 Hz, 1H), 9.45 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H) , 7.77 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.11-7.00 (m, 1H), 6.83 (d, J = 2.3Hz, 2H), 6.69 (t, J = 2.3Hz, 1H), 6.56-6.40 (m, 2H), 6.17 (dd, J = 17.0, 2.0Hz, 1H), 5.65 (dd, J = 10.2 , 2.0Hz, 1H), 3.78 (s, 6H), 2.14 (s, 3H). 13 C NMR (101MHz, DMSO) δ189.71,163.92,160.76,155.45,148.77,142.52,137.24,135.88,132.53,132.08,131.63 , 127.24,127.08,126.20,121.20,114.83,110.98,106.69,105.73,103.59,55.94,19.02.HRMS (ESI) m / z C 26 H 24 N 4 O 4 [M + H] + Calculated value 456.1798; Found Value 457.1868.
化合物7、8、9、11、21和23的合成方法与化合物10类似。Compounds 7, 8, 9, 11, 21, and 23 were synthesized similarly to compound 10.
Figure PCTCN2019090131-appb-000056
Figure PCTCN2019090131-appb-000056
N-(2-((3-(3-甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯 基)丙烯酰胺(7)： 1H NMR(400MHz,DMSO-d 6)δ12.16(d,J＝3.0Hz,1H),9.74(s,1H),8.37-8.17(m,2H),7.82(d,J＝8.1Hz,1H),7.68(d,J＝3.0Hz,1H),7.61(d,J＝7.9Hz,1H),7.47-7.39(m,1H),7.34(dt,J＝7.6,1.2Hz,1H),7.25(dd,J＝2.7,1.5Hz,1H),7.15(ddd,J＝8.2,2.7,1.1Hz,2H),7.05(td,J＝7.7,1.5Hz,1H),6.79(d,J＝8.6Hz,1H),6.48(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,2.0Hz,1H),5.72(dd,J＝10.1,2.0Hz,1H),3.81(s,3H). 13C NMR(101MHz,DMSO)δ189.93,164.20,159.67,153.80,148.21,141.79,134.58,132.64,132.47,132.19,130.08,127.19,125.81,125.37,123.18,123.09,121.27,117.68,114.98,113.73,111.74,107.25,55.79.HRMS(ESI)m/z C 24H 20N 4O 3[M+H] +的计算值412.1535；实测值413.1609. N- (2-((3- (3-methoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (7): 1 H NMR (400MHz, DMSO-d 6 ) δ12.16 (d, J = 3.0Hz, 1H), 9.74 (s, 1H), 8.37-8.17 (m, 2H), 7.82 (d, J = 8.1Hz, 1H) , 7.68 (d, J = 3.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.47-7.39 (m, 1H), 7.34 (dt, J = 7.6, 1.2 Hz, 1H), 7.25 ( dd, J = 2.7, 1.5 Hz, 1H), 7.15 (ddd, J = 8.2, 2.7, 1.1 Hz, 2H), 7.05 (td, J = 7.7, 1.5 Hz, 1H), 6.79 (d, J = 8.6 Hz , 1H), 6.48 (dd, J = 17.0, 10.2 Hz, 1H), 6.23 (dd, J = 17.0, 2.0 Hz, 1H), 5.72 (dd, J = 10.1, 2.0 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101MHz, DMSO) δ 189.93, 164.20, 159.67, 153.80, 148.21, 141.79, 134.58, 132.64, 132.47, 132.19, 130.08, 127.19, 125.81, 125.37, 123.18, 123.09, 121.27, 117.68, 114.98, 113.73 , 111.74, 107.25, 55.79. HRMS (ESI) m / z Calculated value of C 24 H 20 N 4 O 3 [M + H] + 412.1535; found 413.1609.
Figure PCTCN2019090131-appb-000057
Figure PCTCN2019090131-appb-000057
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(8)： 1H NMR(400MHz,氯仿-d)δ12.32(s,1H),8.51(s,1H),8.40(d,J＝8.5Hz,1H),7.64(d,J＝8.1Hz,1H),7.45(s,1H),7.13(d,J＝8.0Hz,1H),7.11-7.01(m,1H),6.89(d,J＝2.3Hz,2H),6.84(td,J＝7.7,1.4Hz,1H),6.68(t,J＝2.3Hz,1H),6.63(d,J＝8.5Hz,1H),6.54(d,J＝2.7Hz,1H),6.36(dd,J＝17.0,1.6Hz,1H),6.25(dd,J＝16.9,9.9Hz,1H),5.70(dd,J＝9.9,1.6Hz,1H),3.85(s,6H). 13C NMR(101MHz,CDCl 3)δ190.28,164.79,160.48,152.72,147.69,142.11,134.91,133.72,132.70,130.38,129.58,128.65,127.15,124.78,124.07,123.30,115.28,112.97,107.73,107.28,103.26,60.50,55.89,31.67,22.74,21.15,14.28,14.21.HRMS(ESI)m/z C 25H 22N 4O 4[M+H] +的计算值442.1641；实测值443.1717. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) acrylamide (8) : 1 H NMR (400MHz, chloroform-d) δ 12.32 (s, 1H), 8.51 (s, 1H), 8.40 (d, J = 8.5Hz, 1H), 7.64 (d, J = 8.1Hz, 1H) , 7.45 (s, 1H), 7.13 (d, J = 8.0Hz, 1H), 7.11-7.01 (m, 1H), 6.89 (d, J = 2.3Hz, 2H), 6.84 (td, J = 7.7, 1.4 Hz, 1H), 6.68 (t, J = 2.3 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 2.7 Hz, 1H), 6.36 (dd, J = 17.0, 1.6 Hz, 1H), 6.25 (dd, J = 16.9, 9.9 Hz, 1H), 5.70 (dd, J = 9.9, 1.6 Hz, 1H), 3.85 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ190 .28,164.79,160.48,152.72,147.69,142.11,134.91,133.72,132.70,130.38,129.58,128.65,127.15,124.78,124.07,123.30,115.28,112.97,107.73,107.28,103.26,60.50,55.89,31.67.22. , 14.28, 14.21. HRMS (ESI) m / z C 25 H 22 N 4 O 4 [M + H] + Calculated 442.1641; Found 443.1717.
Figure PCTCN2019090131-appb-000058
Figure PCTCN2019090131-appb-000058
N-(2-((3-(2,6-二氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(9)： 1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),9.73(s,1H),8.27(s,1H),7.81(d,J＝8.1Hz,1H),7.62(d,J＝8.0Hz,1H),7.48(s,1H),7.15(td,J＝7.7,1.6Hz,1H),7.05(td,J＝7.6,1.5Hz,1H),6.99(s,1H),6.79(d,J＝8.6Hz,1H),6.49(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,2.0Hz,1H),5.72(dd,J＝10.1,2.0Hz,1H),3.95(s,6H). 13C NMR(101MHz,DMSO)δ185.46,164.20,155.03,154.06,148.54,140.20,134.43,132.45,130.31,127.22,125.79,125.31,123.45,123.28,115.42,110.49,110.15,107.51,99.02,57.34.HRMS(ESI)m/z C 25H 20Cl 2N 4O 4[M+H] +的计算值510.0862；实测值511.0934. N- (2-((3- (2,6-dichloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) benzene Group) acrylamide (9): 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.26 (s, 1H), 9.73 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.1 Hz , 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.15 (td, J = 7.7, 1.6 Hz, 1H), 7.05 (td, J = 7.6, 1.5 Hz, 1H) , 6.99 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.49 (dd, J = 17.0, 10.2 Hz, 1H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H), 5.72 ( dd, J = 10.1, 2.0 Hz, 1 H), 3.95 (s, 6 H). 13 C NMR (101 MHz, DMSO) δ 185.46, 164.20, 155.03, 154.06, 148.54, 140.20, 134.43, 132.45, 130.31, 127.22, 125.79, 125.31 , 123.45, 123.28, 115.42, 110.49, 110.15, 107.51, 99.02, 57.34. HRMS (ESI) m / z C 25 H 20 Cl 2 N 4 O 4 [M + H] + Calculated value 510.0862; Found 511.0934.
Figure PCTCN2019090131-appb-000059
Figure PCTCN2019090131-appb-000059
N-(2-((3-(2,6-二氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-3-甲基苯基)丙烯酰胺(11)： 1H NMR(400MHz,DMSO-d 6)δ12.18(s,1H),9.43(s,1H),8.14(s,1H),7.93(s,1H),7.79(d,J＝8.0Hz,1H),7.38(s,1H),7.17(t,J＝7.8Hz,1H),7.12-7.07(m,1H),6.98(s,1H),6.62-6.36(m,2H),6.18(dd,J＝17.0,2.0Hz,1H),5.66(dd,J＝10.2,2.0Hz,1H),3.95(s,6H),2.15(s,3H). 13C NMR(101MHz,DMSO)δ185.37,163.94,155.65,155.00,149.08,140.25,137.36,135.98,132.51,131.45,127.26,127.04,126.30,121.19,115.38,110.14,109.73,106.01,98.97,57.32,18.98. N- (2-((3- (2,6-dichloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino)- 3-methylphenyl) acrylamide (11): 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.18 (s, 1H), 9.43 (s, 1H), 8.14 (s, 1H), 7.93 (s , 1H), 7.79 (d, J = 8.0Hz, 1H), 7.38 (s, 1H), 7.17 (t, J = 7.8Hz, 1H), 7.12-7.07 (m, 1H), 6.98 (s, 1H) , 6.62-6.36 (m, 2H), 6.18 (dd, J = 17.0, 2.0Hz, 1H), 5.66 (dd, J = 10.2, 2.0Hz, 1H), 3.95 (s, 6H), 2.15 (s, 3H ). 13 C NMR (101MHz, DMSO) δ185.37,163.94,155.65,155.00,149.08,140.25,137.36,135.98,132.51,131.45,127.26,127.04,126.30,121.19,115.38,110.14,109.73,106.01,98.97,57.32, 18.98.
Figure PCTCN2019090131-appb-000060
Figure PCTCN2019090131-appb-000060
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-3-甲基苯基)丙酰胺(21)：MS(ESI):459[M+H] +. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -3-methylphenyl) Propionamide (21): MS (ESI): 459 [M + H] + .
Figure PCTCN2019090131-appb-000061
Figure PCTCN2019090131-appb-000061
N-(2-((3-(3,5-二甲氧基苯甲酰)-1-甲基-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(23)： 1H NMR(400MHz,DMSO-d 6)δ9.70(s,1H),8.35(s,1H),8.28(d,J＝8.5Hz,1H),7.91(d,J＝11.6Hz,2H),7.60(d,J＝8.0Hz,1H),7.18(t,J＝7.8Hz,1H),7.05(t,J＝7.7Hz,1H),6.87(s,2H),6.81(d,J＝8.5Hz,1H),6.72(s,1H),6.49(dd,J＝17.1,10.1Hz,1H),6.25(d,J＝16.9Hz,1H),5.73(d,J＝10.3Hz,1H),3.81(s,6H),3.74(s,3H). N- (2-((3- (3,5-dimethoxybenzoyl) -1-methyl-1H-pyrrolo [2,3-b] pyridin-6-yl) amino) phenyl) Acrylamide (23): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (s, 1 H), 8.35 (s, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 11.6 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.87 (s, 2H), 6.81 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 6.49 (dd, J = 17.1, 10.1 Hz, 1H), 6.25 (d, J = 16.9 Hz, 1H), 5.73 (d, J = 10.3Hz, 1H), 3.81 (s, 6H), 3.74 (s, 3H).
Figure PCTCN2019090131-appb-000062
Figure PCTCN2019090131-appb-000062
对于I32、I34-I36、产物12-18来说，R＝4-甲基哌嗪、4-吗啉、4-乙酰哌嗪、4-(1-甲基-1H-吡唑-3-基)；对于产物16-18来说，当R＝4-吗啉时，Ar＝2-氯-3,5-二甲氧基苯基或2,6-二氯-3,5-二甲氧基苯基，当R＝4-(1-甲基-1H-吡唑-3-基)时，Ar＝2,6-二氯-3,5-二甲氧基苯基For I32, I34-I36, products 12-18, R = 4-methylpiperazine, 4-morpholine, 4-acetylpiperazine, 4- (1-methyl-1H-pyrazol-3-yl ); For products 16-18, when R = 4-morpholine, Ar = 2-chloro-3,5-dimethoxyphenyl or 2,6-dichloro-3,5-dimethoxy Phenyl, when R = 4- (1-methyl-1H-pyrazol-3-yl), Ar = 2,6-dichloro-3,5-dimethoxyphenyl
条件和试剂：Conditions and reagents:
(a)Boc 2O,THF,回流,过夜； (a) Boc 2 O, THF, reflux, overnight;
(b)胺,Pd 2(dba) 3,Xant-Phos,Cs 2CO 3,1,4-二氧六环,100摄氏度,过夜； (b) amine, Pd 2 (dba) 3 , Xant-Phos, Cs 2 CO 3 , 1,4-dioxane, 100 degrees Celsius, overnight;
(c)TFA/DCM,室温；(c) TFA / DCM, room temperature;
(d)Pd(dppf)Cl 2,K 2CO 3,1,4-二氧六环/H2O(v:v＝3:1),100摄氏度,微波,2h； (d) Pd (dppf) Cl 2 , K 2 CO 3 , 1,4-dioxane / H2O (v: v = 3: 1), 100 degrees Celsius, microwave, 2h;
(e)Boc 2O,DMAP,DCM,室温； (e) Boc 2 O, DMAP, DCM, room temperature;
(f)Pd(OAc)2,Xant-phos,Cs 2CO 3,1,4-二氧六环,110摄氏度,过夜； (f) Pd (OAc) 2, Xant-phos, Cs 2 CO 3 , 1,4-dioxane, 110 degrees Celsius, overnight;
(g)H 2,Pd/C,EA,室温； (g) H 2 , Pd / C, EA, room temperature;
(h)丙烯酰氯,DIEA,THF,0摄氏度,然后室温；(h) Acryloyl chloride, DIEA, THF, 0 degrees Celsius, and then room temperature;
(i)TFA,DCM,室温；(i) TFA, DCM, room temperature;
(j)SO 2Cl 2,DCM,0摄氏度. (j) SO 2 Cl 2 , DCM, 0 degrees Celsius.
Figure PCTCN2019090131-appb-000063
Figure PCTCN2019090131-appb-000063
条件和试剂：Boc 2O,THF,回流,过夜 Conditions and reagents: Boc 2 O, THF, reflux, overnight
(4-溴-2-硝基苯基)氨基甲酸叔丁酯(I30)：将4-溴-2-硝基苯胺(1.6g，3.8mmol)、Boc 2O(0.91g，0.96mL，4.2mmol)溶于THF，回流搅拌过夜，冷却至室温，浓缩，柱层析纯化得到白色固体0.98g，产率81％。 1H NMR(400MHz,CDCl 3)δ9.57(s,1H),8.52-8.42(m,1H),8.28(d,J＝2.4Hz,1H),7.65(dd,J＝9.2,2.4Hz,1H),1.52(s,9H). 13C NMR(101MHz,CDCl 3)δ151.95,138.54,136.17,135.17,128.27,122.21,113.74,82.31,28.22. (4-Bromo-2-nitrophenyl) carbamic acid tert-butyl ester (I30): 4-bromo-2-nitroaniline (1.6 g, 3.8 mmol), Boc 2 O (0.91 g, 0.96 mL, 4.2 mmol) was dissolved in THF, stirred at reflux overnight, cooled to room temperature, concentrated, and purified by column chromatography to obtain 0.98 g of a white solid with a yield of 81%. 1 H NMR (400MHz, CDCl 3 ) δ 9.57 (s, 1H), 8.52-8.42 (m, 1H), 8.28 (d, J = 2.4Hz, 1H), 7.65 (dd, J = 9.2, 2.4Hz, 1H), 1.52 (s, 9H). 13 C NMR (101MHz, CDCl 3 ) δ151.95,138.54,136.17,135.17,128.27,122.21,113.74,82.31,28.22.
Figure PCTCN2019090131-appb-000064
Figure PCTCN2019090131-appb-000064
条件和试剂：Pd 2(dba) 3,Xant-Phos,Cs 2CO 3,1,4-二氧六环,100摄氏度,过夜 Conditions and reagents: Pd 2 (dba) 3 , Xant-Phos, Cs 2 CO 3 , 1,4-dioxane, 100 ° C, overnight
(4-吗啉代-2-硝基苯基)氨基甲酸叔丁酯(I31b)：将化合物I30(0.50g，1.6mmol)、吗啡啉(0.21g，0.21mL，2.36mmol)、Pd 2(dba) 3(0.15g，0.16mmol)、Xant-Phos(0.18g，0.32mmol)、碳酸铯(1.0g，3.2mmol)溶于无水1,4-二氧六环(16.0mL)，通入氩气除氧。反应液在100℃条件下搅拌过夜，冷却至室温，过滤，往滤液中加入水(50mL)和乙酸乙酯(3×50mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.44g，产率86％。 1H NMR(400MHz,DMSO-d 6)δ9.18(s,1H),7.40(d,J＝9.0Hz,1H),7.36(d,J＝2.9Hz,1H),7.28(dd,J＝9.0,2.9Hz,1H),3.79-3.66(m,4H),3.21-3.09(m,4H),1.41(s,9H). 13C NMR(101MHz,DMSO)δ153.45,148.28,143.34,126.59,123.99,121.07,110.28,80.34,66.38,48.58,28.49. (4-morpholino-2-nitrophenyl) carbamic acid tert-butyl ester (I31b): Compound I30 (0.50 g, 1.6 mmol), morpholine (0.21 g, 0.21 mL, 2.36 mmol), Pd 2 ( dba) 3 (0.15g, 0.16mmol), Xant-Phos (0.18g, 0.32mmol), cesium carbonate (1.0g, 3.2mmol) were dissolved in anhydrous 1,4-dioxane (16.0mL), and passed through Argon is used to remove oxygen. The reaction solution was stirred at 100 ° C overnight, cooled to room temperature, and filtered. Water (50 mL) and ethyl acetate (3 x 50 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.44 g of a yellow solid with a yield of 86%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.18 (s, 1 H), 7.40 (d, J = 9.0 Hz, 1 H), 7.36 (d, J = 2.9 Hz, 1 H), 7.28 (dd, J = 9.0, 2.9Hz, 1H), 3.79-3.66 (m, 4H), 3.21-3.09 (m, 4H), 1.41 (s, 9H). 13 C NMR (101MHz, DMSO) δ153.45, 148.28, 143.34, 126.59, 123.99 , 121.07, 110.28, 80.34, 66.38, 48.58, 28.49.
Figure PCTCN2019090131-appb-000065
Figure PCTCN2019090131-appb-000065
条件和试剂：TFA/DCM,室温Conditions and reagents: TFA / DCM, room temperature
4-吗啉代-2-硝基苯胺(I32b)：将化合物I31b(0.44g)溶于DCM(3mL)，加入三氟乙酸(3mL)，室温搅拌1h，浓缩，加入饱和碳酸氢钠水溶液和乙酸乙酯萃取，收集有机相，依次用水、饱和食盐水洗涤，浓缩得到的黄色固体0.30g，不需经过纯化可直接用于下一步反应。4-morpholino-2-nitroaniline (I32b): Dissolve compound I31b (0.44g) in DCM (3mL), add trifluoroacetic acid (3mL), stir at room temperature for 1h, concentrate, add saturated sodium bicarbonate aqueous solution and It was extracted with ethyl acetate, and the organic phase was collected, washed with water and saturated brine in sequence, and 0.30 g of the obtained yellow solid was concentrated, which was directly used in the next reaction without purification.
Figure PCTCN2019090131-appb-000066
Figure PCTCN2019090131-appb-000066
条件和试剂：Pd(dppf)Cl 2,K 2CO 3,1,4-二氧六环/H2O(v:v＝3:1),100摄氏度,微波,2h Conditions and reagents: Pd (dppf) Cl 2 , K 2 CO 3 , 1,4-dioxane / H2O (v: v = 3: 1), 100 ° C, microwave, 2h
4-(1-甲基-1H-吡唑-3-基)-2-硝基苯胺(I32d)：将4-溴-2-硝基苯胺(0.30g，1.4mmol)、1-甲基-1H-吡唑-5-硼酸频哪醇酯(0.43g，2.1mmol)、Pd(dppf)Cl 2(0.23g，0.28mmol)、碳酸钾(0.57g，4.1mmol)溶于1,4-二氧六环和水(3：1)的混合溶剂(12mL)，通入氩气除氧。反应液在微波反应器中、100℃条件下反应2h，冷却至室温，过滤，往滤液中加入水和乙酸乙酯(3×40mL)萃取，收集有机相，饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.24g，产率79％。 1H NMR(400MHz,DMSO-d 6)δ8.09(d,J＝0.9Hz,1H),8.07(d,J＝2.2Hz,1H),7.79(d,J＝0.8Hz,1H),7.64(dd,J＝8.8,2.2Hz,1H),7.41(s,2H),7.03(d,J＝8.8Hz,1H),3.83(s,3H). 13C NMR(101MHz,DMSO)δ145.19,136.07,134.08,130.81,127.82,121.10,121.00,120.55,120.40,39.16. 4- (1-methyl-1H-pyrazol-3-yl) -2-nitroaniline (I32d): 4-bromo-2-nitroaniline (0.30 g, 1.4 mmol), 1-methyl- 1H-pyrazole-5-boronic acid pinacol ester (0.43 g, 2.1 mmol), Pd (dppf) Cl 2 (0.23 g, 0.28 mmol), potassium carbonate (0.57 g, 4.1 mmol) dissolved in 1,4-di A mixed solvent (12 mL) of oxygen hexacyclic ring and water (3: 1) was purged with argon to remove oxygen. The reaction solution was reacted in a microwave reactor at 100 ° C for 2 hours, cooled to room temperature, and filtered. Water and ethyl acetate (3 × 40 mL) were added to the filtrate for extraction. The organic phase was collected and washed with saturated brine (2 × 20 mL). , Dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.24 g of a yellow solid with a yield of 79%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J = 0.9 Hz, 1 H), 8.07 (d, J = 2.2 Hz, 1 H), 7.79 (d, J = 0.8 Hz, 1 H), 7.64 (dd, J = 8.8, 2.2 Hz, 1H), 7.41 (s, 2H), 7.03 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 145.19, 136.07 , 134.08,130.81,127.82,121.10,121.00,120.55,120.40,39.16.
Figure PCTCN2019090131-appb-000067
Figure PCTCN2019090131-appb-000067
条件和试剂：Boc 2O,DMAP,DCM,室温 Conditions and reagents: Boc 2 O, DMAP, DCM, room temperature
6-氯-3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I33)：将化合物I25b(5.0g，16mmol)溶于DCM(80mL)，依次加入Boc 2O(5.2g，5.5mL，24mmol)、DMAP(0.097g，0.8mmol)，室温搅拌2h后，浓缩，加水和乙酸乙酯萃取，收集有机相，食盐水(2×40mL)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体4.1g，产率62％。 1H NMR(400MHz,CDCl 3)δ8.54(d,J＝8.3Hz,1H),8.16(s,1H),7.35(d,J＝8.3Hz,1H),6.95(d,J＝2.3Hz,2H),6.67(t,J＝2.3Hz,1H),3.84(s,6H),1.68(s,9H). 13C NMR(101MHz,CDCl 3)δ190.17,160.95,148.03,147.35,146.80,140.49,133.83,133.57,120.80,119.98,116.72,106.75,104.64,86.29,55.70,28.05. 6-Chloro-3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid tert-butyl ester (I33): Compound I25b (5.0 g, 16 mmol) was dissolved in DCM (80 mL), Boc 2 O (5.2 g, 5.5 mL, 24 mmol) and DMAP (0.097 g, 0.8 mmol) were added in this order. After stirring at room temperature for 2 h, it was concentrated, extracted with water and ethyl acetate, and the organic phase was collected. , Washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 4.1 g of a yellow solid with a yield of 62%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (d, J = 8.3 Hz, 1 H), 8.16 (s, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 6.95 (d, J = 2.3 Hz , 2H), 6.67 (t, J = 2.3Hz, 1H), 3.84 (s, 6H), 1.68 (s, 9H). 13 C NMR (101MHz, CDCl 3 ) δ 190.17, 160.95, 148.03, 147.35, 146.80, 140.49 , 133.83,133.57,120.80,119.98,116.72,106.75,104.64,86.29,55.70,28.05.
Figure PCTCN2019090131-appb-000068
Figure PCTCN2019090131-appb-000068
条件和试剂：Pd(OAc)2,Xant-phos,Cs 2CO 3,1,4-二氧六环,100摄氏度,过夜 Conditions and reagents: Pd (OAc) 2, Xant-phos, Cs 2 CO 3 , 1,4-dioxane, 100 ° C, overnight
3-(3,5-二甲氧基苯甲酰)-6-((4-吗啉代-2-硝基苯基)氨基)-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I34b)：将化合物I33(0.17g，0.41mmol)、32b(0.088g，0.40mmol)、Pd(OAc) 2(0.009g，0.040mmol)、Xant-Phos(0.047g，0.080mmol)、碳酸铯(0.27g，0.80mmol)溶于无水1,4-二氧六环(4.0mL)，通入氩气除氧。反应液在100℃条件下搅拌过夜，冷却至室温，过滤，往滤液中加入水(20mL)和乙酸乙酯(3×20mL) 萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体0.15g，产率62％。 1H NMR(400MHz,DMSO-d 6)δ9.58(s,1H),8.32(d,J＝8.6Hz,1H),8.13(d,J＝9.2Hz,1H),7.90(s,1H),7.48(d,J＝2.9Hz,1H),7.39(dd,J＝9.2,3.0Hz,1H),7.02(d,J＝8.7Hz,1H),6.95(d,J＝2.3Hz,2H),6.79(t,J＝2.3Hz,1H),3.82(s,6H),3.79-3.73(m,4H),3.18-3.11(m,4H),1.49(s,9H). 13C NMR(101MHz,DMSO)δ190.11,161.01,153.22,146.61,146.19,141.12,140.40,128.41,125.24,123.30,116.81,113.82,110.49,110.15,106.93,85.49,66.47,56.10,49.06,27.98. 3- (3,5-dimethoxybenzoyl) -6-((4-morpholino-2-nitrophenyl) amino) -1H-pyrrolo [2,3-b] pyridine-1 -Tert-butyl formate (I34b): Compound I33 (0.17 g, 0.41 mmol), 32b (0.088 g, 0.40 mmol), Pd (OAc) 2 (0.009 g, 0.040 mmol), Xant-Phos (0.047 g, 0.080 mmol), cesium carbonate (0.27 g, 0.80 mmol) was dissolved in anhydrous 1,4-dioxane (4.0 mL), and argon was passed to remove oxygen. The reaction solution was stirred overnight at 100 ° C, cooled to room temperature, and filtered. Water (20 mL) and ethyl acetate (3 x 20 mL) were added to the filtrate for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 0.15 g of a yellow solid with a yield of 62%. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.90 (s, 1H) , 7.48 (d, J = 2.9 Hz, 1H), 7.39 (dd, J = 9.2, 3.0 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.3 Hz, 2H) , 6.79 (t, J = 2.3Hz, 1H), 3.82 (s, 6H), 3.79-3.73 (m, 4H), 3.18-3.11 (m, 4H), 1.49 (s, 9H). 13 C NMR (101MHz , DMSO) δ190.11,161.01,153.22,146.61,146.19,141.12,140.40,128.41,125.24,123.30,116.81,113.82,110.49,110.15,106.93,85.49,66.47,56.10,49.06,27.98.
Figure PCTCN2019090131-appb-000069
Figure PCTCN2019090131-appb-000069
条件和试剂：H 2,Pd/C,EA,室温 Conditions and reagents: H 2 , Pd / C, EA, room temperature
6-((2-氨基-4-吗啉代苯基)氨基)-3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I35b)：将化合物I34b(0.15g，0.25mmol)溶于乙酸乙酯(5mL)，加入10％Pd/C，氢气(1atm)还原室温搅拌过夜，过滤，收集滤液，浓缩得到白色固体中间体I35b(0.1g)，不需经过纯化可直接用于下一步反应。6-((2-amino-4-morpholinophenyl) amino) -3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridine-1- Tert-butyl formate (I35b): Compound I34b (0.15g, 0.25mmol) was dissolved in ethyl acetate (5mL), 10% Pd / C was added, and hydrogen (1atm) was reduced to room temperature and stirred overnight. The filtrate was collected and concentrated to obtain The white solid intermediate I35b (0.1g) was used directly in the next step without further purification.
Figure PCTCN2019090131-appb-000070
Figure PCTCN2019090131-appb-000070
条件和试剂：DIEA,THF,0摄氏度,然后室温Conditions and reagents: DIEA, THF, 0 ° C, then room temperature
6-((2-丙烯酰胺-4-吗啉代苯基)氨基)-3-(3,5-二甲氧基苯甲酰)-1H- 吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(I36b)：将化合物I35b(0.1g，0.18mmol)溶于四氢呋喃(2.0mL)，冰水浴条件下，依次加入DIEA(60μL，0.36mmol)和丙烯酰氯(18μL，0.22mmol)，室温反应30min。浓缩后加入水(10mL)和乙酸乙酯(3×10mL)萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体70mg，产率62％。MS(ESI):628[M+H] +. 6-((2-acrylamide-4-morpholinophenyl) amino) -3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridine-1 -Tert-butyl formate (I36b): Compound I35b (0.1 g, 0.18 mmol) was dissolved in tetrahydrofuran (2.0 mL), and DIEA (60 μL, 0.36 mmol) and acryloyl chloride (18 μL, 0.22 mmol) were sequentially added under ice-water bath conditions. , Room temperature reaction for 30min. After concentration, water (10 mL) and ethyl acetate (3 × 10 mL) were added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 70 mg of a white solid with a yield of 62%. MS (ESI): 628 [M + H] + .
Figure PCTCN2019090131-appb-000071
Figure PCTCN2019090131-appb-000071
条件和试剂：TFA/DCM,室温Conditions and reagents: TFA / DCM, room temperature
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-吗啉代苯基)丙烯酰胺(13)：将化合物I36b(70mg，0.11mmol)溶于DCM(1.0mL)，加入三氟乙酸(1.0mL)，室温搅拌1h，浓缩，加入饱和碳酸氢钠水溶液和乙酸乙酯萃取，收集有机相，依次用水、饱和食盐水洗涤，浓缩得到的白色固体(63mg)，取部分产物通过柱层析纯化，用于测试活性，其余产物不需经过纯化直接用于下一步反应。 1H NMR(400MHz,氯仿-d)δ12.20(s,1H),8.50(s,1H),8.40(d,J＝8.5Hz,1H),7.55(d,J＝8.9Hz,1H),7.14(s,1H),6.94(d,J＝2.3Hz,2H),6.77(s,1H),6.73-6.66(m,2H),6.56(d,J＝8.5Hz,1H),6.50-6.43(m,1H),6.41(d,J＝1.5Hz,1H),6.30(dd,J＝16.9,10.1Hz,1H),5.76(dd,J＝10.0,1.5Hz,1H),3.88(s,6H),3.70-3.61(m,4H),2.70(t,J＝4.8Hz,4H). 13C NMR(101MHz,CDCl 3)δ189.85,164.63,160.61,153.72,148.92,147.67,142.21,133.72,132.10,131.56,130.60,128.91,128.59,125.62,115.23,115.02,112.46,110.76,107.57,107.17,103.38,66.69,56.01,49.25. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -5-morpholinophenyl ) Acrylamide (13): Dissolve compound I36b (70 mg, 0.11 mmol) in DCM (1.0 mL), add trifluoroacetic acid (1.0 mL), stir at room temperature for 1 h, concentrate, and add saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to extract The organic phase was collected, washed sequentially with water and saturated brine, and concentrated to obtain a white solid (63 mg). Part of the product was purified by column chromatography for testing activity, and the remaining products were used in the next reaction without purification. 1 H NMR (400MHz, chloroform-d) δ 12.20 (s, 1H), 8.50 (s, 1H), 8.40 (d, J = 8.5Hz, 1H), 7.55 (d, J = 8.9Hz, 1H), 7.14 (s, 1H), 6.94 (d, J = 2.3Hz, 2H), 6.77 (s, 1H), 6.73-6.66 (m, 2H), 6.56 (d, J = 8.5Hz, 1H), 6.50-6.43 (m, 1H), 6.41 (d, J = 1.5 Hz, 1H), 6.30 (dd, J = 16.9, 10.1 Hz, 1H), 5.76 (dd, J = 10.0, 1.5 Hz, 1H), 3.88 (s, 6H), 3.70-3.61 (m, 4H), 2.70 (t, J = 4.8Hz, 4H). 13 C NMR (101MHz, CDCl 3 ) δ189.85,164.63,160.61,153.72,148.92,147.67,142.21,133.72,132.10 , 131.56,130.60,128.91,128.59,125.62,115.23,115.02,112.46,110.76,107.57,107.17,103.38,66.69,56.01,49.25.
化合物12、14、15和20的合成方法与化合物13类似。 Compounds 12, 14, 15 and 20 were synthesized in a similar manner to compound 13.
Figure PCTCN2019090131-appb-000072
Figure PCTCN2019090131-appb-000072
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺(12)：白色固体。 1H NMR(400MHz,DMSO-d 6)δ12.08(s,1H),9.65(s,1H),8.21(d,J＝8.6Hz,1H),7.98(s,1H),7.68(d,J＝2.4Hz,1H),7.44(d,J＝8.8Hz,1H),7.38-7.34(m,1H),6.86(d,J＝2.3Hz,2H),6.81(dd,J＝8.9,2.8Hz,1H),6.71(t,J＝2.3Hz,1H),6.63(d,J＝8.6Hz,1H),6.47(dd,J＝17.0,10.2Hz,1H),6.22(dd,J＝17.0,2.0Hz,1H),5.71(dd,J＝10.1,2.0Hz,1H),3.80(s,6H),3.18-3.07(m,4H),2.57(s,4H). 13C NMR(101MHz,DMSO)δ189.74,164.00,160.79,155.02,148.54,147.98,142.54,132.54,132.32,132.06,127.22,125.88,125.75,114.92,113.42,111.61,111.15,106.69,106.27,103.58,55.95,54.92,48.84,45.87.MS(ESI):541[M+H] +. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -5- (4-methyl Piperazin-1-yl) phenyl) acrylamide (12): white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.08 (s, 1H), 9.65 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.44 (d, J = 8.8Hz, 1H), 7.38-7.34 (m, 1H), 6.86 (d, J = 2.3Hz, 2H), 6.81 (dd, J = 8.9, 2.8 Hz, 1H), 6.71 (t, J = 2.3 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.47 (dd, J = 17.0, 10.2 Hz, 1H), 6.22 (dd, J = 17.0 , 2.0Hz, 1H), 5.71 ( dd, J = 10.1,2.0Hz, 1H), 3.80 (s, 6H), 3.18-3.07 (m, 4H), 2.57 (s, 4H). 13 C NMR (101MHz, (DMSO) δ189.74,164.00,160.79,155.02,148.54,147.98,142.54,132.54,132.32,132.06,127.22,125.88,125.75,114.92,113.42,111.61,111.15,106.69,106.27,103.58,55.95,54.92,48.84,84.84 MS (ESI): 541 [M + H] + .
Figure PCTCN2019090131-appb-000073
Figure PCTCN2019090131-appb-000073
N-(5-(4-乙酰基哌嗪-1-基)-2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)苯基)丙烯酰胺(14)：白色固体。 1H NMR(400MHz,氯仿-d)δ12.11(s,1H),8.64(s,1H),8.40(d,J＝8.5Hz,1H), 7.52(d,J＝8.8Hz,1H),7.16(s,1H),6.96-6.87(m,3H),6.73-6.64(m,2H),6.64-6.52(m,2H),6.41(dd,J＝16.9,1.5Hz,1H),6.29(dd,J＝16.9,10.1Hz,1H),5.74(dd,J＝9.9,1.5Hz,1H),3.87(s,6H),3.55(t,J＝5.2Hz,2H),3.40(t,J＝5.1Hz,2H),2.76(t,J＝5.2Hz,2H),2.66(t,J＝5.3Hz,2H),2.06(s,3H). 13C NMR(101MHz,CDCl 3)δ189.84,169.08,164.62,160.64,153.79,148.40,147.76,142.16,133.64,131.96,131.76,130.72,128.49,126.62,125.52,115.61,115.29,112.46,111.84,107.47,107.09,103.26,55.97,49.62,49.25,46.06,41.23,21.32,14.26. N- (5- (4-acetylpiperazin-1-yl) -2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridine -6-yl) amino) phenyl) acrylamide (14): white solid. 1 H NMR (400MHz, chloroform-d) δ 12.11 (s, 1H), 8.64 (s, 1H), 8.40 (d, J = 8.5Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.16 (s, 1H), 6.96-6.87 (m, 3H), 6.73-6.64 (m, 2H), 6.64-6.52 (m, 2H), 6.41 (dd, J = 16.9, 1.5Hz, 1H), 6.29 ( dd, J = 16.9, 10.1 Hz, 1H), 5.74 (dd, J = 9.9, 1.5 Hz, 1H), 3.87 (s, 6H), 3.55 (t, J = 5.2 Hz, 2H), 3.40 (t, J = 5.1Hz, 2H), 2.76 (t, J = 5.2Hz, 2H), 2.66 (t, J = 5.3Hz, 2H), 2.06 (s, 3H). 13 C NMR (101MHz, CDCl 3 ) δ189.84,169.08 , 164.62,160.64,153.79,148.40,147.76,142.16,133.64,131.96,131.76,130.72,128.49,126.62,125.52,115.61,115.29,112.46,111.84,107.47,107.09,103.26,55.97,49.62,49.25,46.06. , 21.32, 14.26.
Figure PCTCN2019090131-appb-000074
Figure PCTCN2019090131-appb-000074
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-(1-甲基-1H-吡唑-3-基)苯基)丙烯酰胺(15)：白色固体。MS(ESI):523[M+H] +. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -5- (1-methyl -1H-pyrazol-3-yl) phenyl) acrylamide (15): white solid. MS (ESI): 523 [M + H] + .
Figure PCTCN2019090131-appb-000075
Figure PCTCN2019090131-appb-000075
N-(2-((3-(3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙酰胺(20)：白色固体。MS(ESI):543[M+H] +. N- (2-((3- (3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -5- (4-methyl Piperazin-1-yl) phenyl) propionamide (20): white solid. MS (ESI): 543 [M + H] + .
Figure PCTCN2019090131-appb-000076
Figure PCTCN2019090131-appb-000076
条件和试剂：SO 2Cl 2,DCM,0摄氏度 Conditions and reagents: SO 2 Cl 2 , DCM, 0 degrees Celsius
N-(2-((3-(2,6-二氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-吗啉代苯基)丙烯酰胺(17)：将化合物13(50mg，0.095mmol)溶于无水二氯甲烷(2.0mL)，在0℃下滴加磺酰氯(32mg，19μL，0.24mmol)，保持在0℃条件下搅拌0.5h，加入饱和碳酸氢钠水溶液(10mL)和二氯甲烷(10mL)萃取，收集有机相，依次用水、饱和食盐水洗涤，浓缩柱层析分离纯化得到白色固体11mg，产率19％。MS(ESI):596[M+H] +. N- (2-((3- (2,6-dichloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino)- 5-morpholinophenyl) acrylamide (17): Compound 13 (50 mg, 0.095 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), and sulfonyl chloride (32 mg, 19 μL, 0.24 mmol) was added dropwise at 0 ° C. ), Keep stirring at 0 ° C for 0.5h, add saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (10mL) for extraction, collect the organic phase, wash with water and saturated brine in sequence, and isolate and purify by column chromatography to obtain white 11 mg of solid, 19% yield. MS (ESI): 596 [M + H] + .
化合物16、18、22、19的合成方法与化合物17类似。Compounds 16, 18, 22, and 19 were synthesized similarly to compound 17.
Figure PCTCN2019090131-appb-000077
Figure PCTCN2019090131-appb-000077
N-(2-((3-(2-氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-吗啉代苯基)丙烯酰胺(16)：白色固体。 1H NMR(400MHz,DMSO-d 6)δ12.12(s,1H),9.61(s,1H),8.08(s,1H),7.98(s,1H),7.44(d,J＝8.9Hz,1H),7.36(d,J＝3.1Hz,2H),6.85-6.77(m,3H),6.65-6.57(m,2H),6.46(dd,J＝16.9,10.2Hz,1H),6.21(dd,J＝16.9,2.0Hz,1H),5.70(d,J＝11.1Hz,1H),3.88(s,3H),3.78(s,3H),3.74(t,J＝4.8Hz,4H),3.06(t,J＝4.8Hz,4H).MS(ESI):562[M+H] +. N- (2-((3- (2-chloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino) -5- Phenolinyl) acrylamide (16): white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.12 (s, 1H), 9.61 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.44 (d, J = 8.9Hz, 1H), 7.36 (d, J = 3.1Hz, 2H), 6.85-6.77 (m, 3H), 6.65-6.57 (m, 2H), 6.46 (dd, J = 16.9, 10.2Hz, 1H), 6.21 (dd , J = 16.9, 2.0Hz, 1H), 5.70 (d, J = 11.1Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.74 (t, J = 4.8Hz, 4H), 3.06 (t, J = 4.8Hz, 4H) .MS (ESI): 562 [M + H] + .
Figure PCTCN2019090131-appb-000078
Figure PCTCN2019090131-appb-000078
N-(2-((3-(2,6-二氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-(1-甲基-1H-吡唑-3-基)苯基)丙烯酰胺(18)： 1H NMR(400MHz,DMSO-d 6)δ12.25(s,1H),9.75(s,1H),8.24(s,1H),8.07(s,1H),7.79(d,J＝3.3Hz,3H),7.48(s,1H),7.36(dd,J＝8.4,2.1Hz,1H),7.00(s,1H),6.79(d,J＝8.6Hz,1H),6.51(dd,J＝17.0,10.2Hz,1H),6.26(dd,J＝17.0,2.0Hz,1H),5.75(dd,J＝10.1,2.0Hz,1H),3.96(s,6H),3.86(s,3H). N- (2-((3- (2,6-dichloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino)- 5- (1-methyl-1H-pyrazol-3-yl) phenyl) acrylamide (18): 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.25 (s, 1H), 9.75 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.79 (d, J = 3.3Hz, 3H), 7.48 (s, 1H), 7.36 (dd, J = 8.4, 2.1Hz, 1H), 7.00 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.51 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd, J = 17.0, 2.0 Hz, 1H), 5.75 (dd , J = 10.1, 2.0Hz, 1H), 3.96 (s, 6H), 3.86 (s, 3H).
Figure PCTCN2019090131-appb-000079
Figure PCTCN2019090131-appb-000079
N-(2-((3-(2,6-二氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺(22)：MS(ESI):609[M+H]+.N- (2-((3- (2,6-dichloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino)- 5- (4-methylpiperazin-1-yl) phenyl) acrylamide (22): MS (ESI): 609 [M + H] +.
Figure PCTCN2019090131-appb-000080
Figure PCTCN2019090131-appb-000080
N-(2-((3-(2,6-二氯-3,5-二甲氧基苯甲酰)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-3-甲基-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺(19)：MS(ESI):623[M+H]+.N- (2-((3- (2,6-dichloro-3,5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-6-yl) amino)- 3-methyl-5- (4-methylpiperazin-1-yl) phenyl) acrylamide (19): MS (ESI): 623 [M + H] +.
生物活性测试Biological activity test
(I)激酶活性检测实验(I) Kinase activity detection experiment
实验材料：PE Envision酶标仪；384孔白板(OptiPlate TM-384)；FGFR4激酶(08-136，Carna)，Cisbio HTRF试剂盒(Cisbio Assays62TK0PEB)Experimental materials: PE Envision microplate reader; 384-well white plate (OptiPlate TM-384); FGFR4 kinase (08-136, Carna), Cisbio HTRF kit (CisbioAssays62TK0PEB)
实验方法：按照
Figure PCTCN2019090131-appb-000081
KinEase TM assay标准方法进行。酶促反应步骤：在384孔板中依次加入用kinase buffer稀释后的浓度梯度抑制剂(30μM到0.1nM，3.3倍稀释12个浓度梯度，4μL)，FGFR4激酶(2ng/孔，2μL)，底物(1μM)和ATP(120μM)的1:1混合液(4μL)，震荡离心后25度孵育45min。检测步骤：加入预先1：1混合的Eu 3+鳌合抗体(5μL)和streptavidin-XL665(0.125μM，5μL)终止反应，室温静置1h后于PE Envision酶标仪读板。以浓度为横坐标，615nm/665nm信号值为纵坐标用GraphPad Prism 5.0拟合曲线，计算IC 50值。 Experimental method: According to
Figure PCTCN2019090131-appb-000081
KinEase ™ assay was performed using standard methods. Enzymatic reaction steps: In a 384-well plate, sequentially add a concentration gradient inhibitor diluted with kinase buffer (30 μM to 0.1 nM, 3.3-fold dilution of 12 concentration gradients, 4 μL), FGFR4 kinase (2ng / well, 2 μL), bottom A 1: 1 mixture (4 μL) of the substance (1 μM) and ATP (120 μM) was incubated for 45 min at 25 ° C with shaking and centrifugation. Detection steps: adding a 1: 1 mixture of Eu 3+ chelating antibody (5 μL) and streptavidin-XL665 (0.125 μM, 5 μL) in advance to stop the reaction. After standing at room temperature for 1 hour, read the plate on a PE Envision microplate reader. Using the concentration as the abscissa and the signal value of 615nm / 665nm as the ordinate, the curve was fitted with GraphPad Prism 5.0, and the IC 50 value was calculated.
Figure PCTCN2019090131-appb-000082
Figure PCTCN2019090131-appb-000082
Figure PCTCN2019090131-appb-000083
Figure PCTCN2019090131-appb-000083
Figure PCTCN2019090131-appb-000084
Figure PCTCN2019090131-appb-000084
Figure PCTCN2019090131-appb-000085
Figure PCTCN2019090131-appb-000085
注：“+”表示IC 50>1000nM，“++”表示IC 50＝100～1000nM，“+++”表示IC 50＝10～100nM，“++++”表示IC 50<10nM，“ND”表示还未测IC 50值。 Note: “+” means IC 50 > 1000nM, “++” means IC 50 = 100 ～ 1000nM, “+++” means IC 50 = 10 ～ 100nM, “++++” means IC 50 <10nM, “ND "Indicates that the IC 50 value has not been measured.
(II)细胞增殖抑制实验(II) Cell proliferation inhibition experiment
实验材料：HUH-7细胞(中科院上海细胞库)，MDA-MB-453细胞(中科院上海细胞库)，DMEM培养基(11995065，Gibco)，Leibovitz's L-15培养基(11415064，Gibco)，检测试剂(G7570，Promega)。Experimental materials: HUH-7 cells (Shanghai Cell Bank of the Chinese Academy of Sciences), MDA-MB-453 cells (Shanghai Cell Bank of the Chinese Academy of Sciences), DMEM medium (11995065, Gibco), Leibovitz's L-15 medium (11415064, Gibco), detection reagents (G7570, Promega).
实验方法：胰蛋白酶消化处理贴壁细胞后，加入含血清的完全培养基终止处理，收集细胞，离心(1000×rpm)，将细胞悬浮分散在新鲜完全培养基中进行细胞计数，并将细胞稀释至5×10 4个/mL。在96孔黑板中，每孔加入100μL上述细胞稀释悬浮液或不含细胞的培养基，37℃培养过夜。加入用培养基稀释后的不同浓度抑制剂(50μL)或DMSO(50μL)，37℃培养72h。将96孔板静置室温平衡0.5h后加入检测试剂(40μL)，充分混匀后，静置1h，于酶标仪上读板，以DMSO孔信号值为阳性对照，计算生长抑制率。用GraphPad Prism5.0以抑制率对抑制剂浓度的对数作图拟合，计算细胞EC 50值。 Experimental method: After trypsin digestion of adherent cells, add complete serum-containing medium to terminate the treatment. Collect the cells, centrifuge (1000 × rpm), suspend and disperse the cells in fresh complete medium for cell counting, and dilute the cells. To 5 x 10 4 cells / mL. In a 96-well blackboard, add 100 μL of the above-mentioned cell dilution suspension or cell-free medium to each well and incubate at 37 ° C overnight. Inhibitors (50 μL) or DMSO (50 μL) at different concentrations diluted with the culture medium were added and cultured at 37 ° C. for 72 h. The 96-well plate was allowed to stand at room temperature for 0.5h, and the detection reagent (40 μL) was added. After thorough mixing, the plate was allowed to stand for 1h. The plate was read on a microplate reader and the DMSO well signal was used as a positive control to calculate the growth inhibition rate. GraphPad Prism 5.0 was used to fit the logarithm of the inhibitory rate to the inhibitor concentration, and the cell EC 50 values were calculated.
本发明化合物1-22具有良好的细胞增殖抑制作用，部分化合物在细胞系HuH-7和MDA-MB-453的结果如下。The compound 1-22 of the present invention has a good inhibitory effect on cell proliferation. The results of some compounds in the cell lines HuH-7 and MDA-MB-453 are as follows.
Figure PCTCN2019090131-appb-000086
Figure PCTCN2019090131-appb-000086
注：“+”表示IC 50>1000nM，“++”表示IC 50＝100～1000nM，“+++” 表示IC 50<100nM。 Note: “+” means IC 50 > 1000nM, “++” means IC 50 = 100 ～ 1000nM, “+++” means IC 50 <100nM.
(III)时间依赖性抑制实验(III) Time-dependent inhibition experiment
Staurosporine(星孢菌素，非共价抑制剂，250nM)，化合物11(40nM)和kinase buffer(阳性对照)与FGFR4激酶孵育不同时间(0、1min、2min、4min、8min、16min、30min、45min)后加入ATP(120μM)和底物(1μM)1：1混合液(4μL)启动酶促反应。分别震荡离心后25度孵育45min。加入预先1：1混合的Eu 3+鳌合抗体(5μL)和streptavidin-XL665(0.125μM，5μL)终止反应。各时间点与阳性对照信号的比值计算抑制率((1-signal sample/signal control)×100％)，用GraphPad Prism 5.0以抑制率对时间作图拟合得到时间依赖性抑制曲线。化合物11对FGFR4的抑制活性强度随着化合物11与FGFR4激酶的共孵育时间增长而加强；但是非共价抑制剂Staurosporine对FGFR4的抑制强度不随共孵育时间而变化。 Staurosporine (astrosporine, non-covalent inhibitor, 250nM), compound 11 (40nM) and kinase buffer (positive control) were incubated with FGFR4 kinase at different times (0, 1min, 2min, 4min, 8min, 16min, 30min, 45min ) After adding ATP (120 μM) and substrate (1 μM) 1: 1 mixture (4 μL) to start the enzymatic reaction. Incubate for 45min at 25 ° C after shaking and centrifugation. The reaction was stopped by adding a previously mixed 1: 1 Eu 3+ chelating antibody (5 μL) and streptavidin-XL665 (0.125 μM, 5 μL). The ratio of each time point to the positive control signal was used to calculate the inhibition rate ((1-signal sample / signal control ) × 100%), and GraphPad Prism 5.0 was used to fit the inhibition rate against time to obtain a time-dependent inhibition curve. The inhibitory activity of compound 11 on FGFR4 increased as the co-incubation time of compound 11 and FGFR4 kinase increased; but the inhibitory intensity of non-covalent inhibitor Staurosporine on FGFR4 did not change with the co-incubation time.

Claims (10)

  1. 一种式(I)所示的化合物、其盐或其立体异构体A compound represented by formula (I), a salt thereof or a stereoisomer thereof
    Figure PCTCN2019090131-appb-100001
    Figure PCTCN2019090131-appb-100001
    G 1和G 2彼此独立地，相同地或不同地，选自H，C(O)和S(O) 2； G 1 and G 2 are independently, identically or differently selected from H, C (O) and S (O) 2 ;
    L 1和L 2彼此独立地，相同地或不同地，选自任选地被C 1-3烷基取代的C 2-3烯基、C 0-3烷基-C 2-3烯基和C 1-3烷基-NHC(O)-C 2-3烯基； L 1 and L 2 are independently of each other, identically or differently, selected from C 2-3 alkenyl, C 0-3 alkyl-C 2-3 alkenyl, and optionally substituted with C 1-3 alkyl C 1-3 alkyl-NHC (O) -C 2-3 alkenyl;
    前提是当G 1为H时，L 1不存在，以及当G 2为H时，L 2不存在。 The premise is that when G 1 is H, L 1 does not exist, and when G 2 is H, L 2 does not exist.
    其中，among them,
    Ar是5或6元单环芳香环，Ar is a 5- or 6-membered monocyclic aromatic ring,
    例如：呋喃、吡咯、噻吩、咪唑、吡唑、噁唑、异噁唑、噻唑、苯、吡啶、吡嗪、嘧啶、哒嗪、三唑，For example: furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole,
    优选：苯、吡啶；Preferred: benzene, pyridine;
    R 1选自H、卤素(优选-Cl),-OH,-C 1-4烷基,-C 1-4烷基氧基,
    Figure PCTCN2019090131-appb-100002
    Figure PCTCN2019090131-appb-100003
    R 1 is selected from H, halogen (preferably -Cl), -OH, -C 1-4 alkyl, -C 1-4 alkyloxy,
    Figure PCTCN2019090131-appb-100002
    Figure PCTCN2019090131-appb-100003
    m是0，1，2，3，4，5的整数；m is an integer of 0,1,2,3,4,5;
    W 1是CH,CR 1或N； W 1 is CH, CR 1 or N;
    W 2是CH,CR 1或N； W 2 is CH, CR 1 or N;
    W 3是CH,CR 1或N； W 3 is CH, CR 1 or N;
    W 4是CH,CR 1或N； W 4 is CH, CR 1 or N;
    W 5是CH,CR 1或N； W 5 is CH, CR 1 or N;
    W 6是CH,CR 1或N； W 6 is CH, CR 1 or N;
    W 7是CH,CR 1或N； W 7 is CH, CR 1 or N;
    L选自：键,-O-,-NH-,-S-,-CH 2-,-CH＝CH-,-CH≡CH-,-C(CH 3)H-,-C(CH 3) 2-,-C(CH 2-CH 2)-,-CClH-,-CCl 2-,-CO-,-SO-,和-SO 2-； L is selected from: bond, -O-, -NH-, -S-, -CH 2- , -CH = CH-, -CH≡CH-, -C (CH 3 ) H-,-C (CH 3 ) 2 -,-C (CH 2 -CH 2 )-,-CClH-,-CCl 2 -,-CO-,-SO-, and -SO 2- ;
    n是0，1，2，3，4，5的整数；n is an integer of 0,1,2,3,4,5;
    R 2选自H、卤素(优选-Cl),-OH,-C 1-4烷基,-C 1-4烷基氧基,
    Figure PCTCN2019090131-appb-100004
    Figure PCTCN2019090131-appb-100005
    R 2 is selected from H, halogen (preferably -Cl), -OH, -C 1-4 alkyl, -C 1-4 alkyloxy,
    Figure PCTCN2019090131-appb-100004
    Figure PCTCN2019090131-appb-100005
    R 3选自H、-C 1-4烷基。 R 3 is selected from H and -C 1-4 alkyl.
  2. 前述权利要求中任一项的化合物、其盐或其立体异构体，A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
    其中，G 2是H，L 2不存在。 Among them, G 2 is H, and L 2 does not exist.
  3. 前述权利要求中任一项的化合物、其盐或其立体异构体，A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
    其中W 1,W 2,W 3,W 4,W 5,W 6,W 7都是CH。 W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , and W 7 are all CH.
  4. 前述权利要求中任一项的化合物、其盐或其立体异构体，A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
    其中R 3是H。 Where R 3 is H.
  5. 前述权利要求中任一项的化合物、其盐或其立体异构体，A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
    其中-N(G 1L 1)(G 2L 2)是-NH-CO-C 2-3烯基。 Where -N (G 1 L 1 ) (G 2 L 2 ) is -NH-CO-C 2-3 alkenyl.
  6. 前述权利要求中任一项的化合物、其盐或其立体异构体，A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
    其中Ar是苯基。Where Ar is phenyl.
  7. 一种化合物、其盐或其立体异构体，其中所述化合物选自下述化合物1-23：A compound, a salt thereof, or a stereoisomer thereof, wherein the compound is selected from the following compounds 1-23:
    Figure PCTCN2019090131-appb-100006
    Figure PCTCN2019090131-appb-100006
    Figure PCTCN2019090131-appb-100007
    Figure PCTCN2019090131-appb-100007
    Figure PCTCN2019090131-appb-100008
    Figure PCTCN2019090131-appb-100008
    Figure PCTCN2019090131-appb-100009
    Figure PCTCN2019090131-appb-100009
  8. 一种药物组合物，其包括前述权利要求中任一项所述的化合物、其盐或其立体异构体，和药学上可接受的载体。A pharmaceutical composition comprising a compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  9. 前述权利要求中任一项所述的化合物、其盐或其立体异构体，或前述权利要求中任一项所述的药物组合物在制备用于治疗由FGFR-4介导的病状、以FGFR-4过表达为特征的病状、以FGFR4扩增为特征的病状、由FGF19介导的病状、以扩增的FGF19为特征的病状或以FGF19过表达为特征的病状的药物中的用途。The compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof, or the pharmaceutical composition according to any one of the preceding claims in the preparation for treating a condition mediated by FGFR-4, to Use of a medicament for a condition characterized by FGFR-4 overexpression, a condition characterized by FGFR4 amplification, a condition mediated by FGF19, a condition characterized by amplified FGF19, or a condition characterized by FGF19 overexpression.
  10. 前述权利要求中任一项所述的用途，其中所述病状是肝细胞癌、乳腺癌、卵巢癌、肺癌、肝癌、肉瘤或高脂血症。The use according to any one of the preceding claims, wherein the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma or hyperlipidemia.
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